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Buneeva, O. A., L. N. Aksenova i A. E. Medvedev. "A Simple Approach for Pilot Analysis of Time-dependent Enzyme Inhibition: Discrimination Between Mechanism-based Inactivation and Tight Binding Inhibitor Behavior". Biomedical Chemistry: Research and Methods 3, nr 1 (2020): e00115. http://dx.doi.org/10.18097/bmcrm00115.
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The increase in enzyme inhibition developed during prolonged incubation of an enzyme preparation with a chemical substance may be associated with both the non-covalent and also with covalent enzyme-inhibitor complex formation. The latter case involves catalytic conversion of a mechanism-based irreversible inhibitor (a poor substrate) into a reactive species forming covalent adduct(s) with the enzyme and thus irreversibly inactivating the enzyme molecule. Using a simple approach, based on comparison of enzyme inhibition after preincubation with a potential inhibitor at 4ºC or 37ºC we have analyzed inhibition of monoamine oxidase A (MAO A) by known MAO inhibitors pargyline and pirlindole (pyrazidol). MAO A inhibitory activity of pirlindole (reversible tight binding inhibitor of MAO A) assayed after mitochondrial wash was basically the same for the incubation at both 4ºC and 37ºC. In contrast to pirlindole, the effect of pargyline (mechanism based irreversible MAO inhibitor) strongly depended on the temperature of the incubation medium. At 37ºC the residual activity MAO A in the mitochondrial fraction after washing was significantly lower than in the mitochondrial samples incubated with pargyline at 4ºC. Results of this study suggest that using analysis of both time- and temperature-dependence of inhibition it is possible to discriminate mechanism-based irreversible inhibition and reversible tight binding inhibition of target enzym
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Gledhill, L., P. Williams i B. W. Bycroft. "Irreversible inactivation of β-lactamase I from Bacillus cereus by chlorinated 6-spiroepoxypenicillins". Biochemical Journal 276, nr 3 (15.06.1991): 801–7. http://dx.doi.org/10.1042/bj2760801.
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On incubation of the chlorinated 6-spiroepoxypenicillin anilides (I) and (II) [formula: see text] with beta-lactamase 1 from Bacillus cereus, three distinct processes are observed. The inhibitors act as (a) substrates, the turnover of which respectively results in a single product, namely 6-substituted 2(H)-3,4-dihydro-1,4-thiazine, (b) a transiently inhibited enzyme complex, and finally (c) an irreversibly inactivated enzyme complex. Although differing only in their stereochemistry at one centre, the anilide (K) is a more potent irreversible inactivator of beta-lactamase I than is compound (II). Analysis of irreversibly inactivated beta-lactamase I by isoelectric focusing and inspection of peptide fragmentation maps indicated that irreversible inactivation appears to be accompanied by covalent modification. These studies reveal that the chlorinated 6-spiroepoxypenicillin anilide (I) is a mechanism-based beta-lactamase inhibitor.
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Rožman, Kaja, Evan M. Alexander, Eva Ogorevc, Krištof Bozovičar, Izidor Sosič, Courtney C. Aldrich i Stanislav Gobec. "Psoralen Derivatives as Inhibitors of Mycobacterium tuberculosis Proteasome". Molecules 25, nr 6 (12.03.2020): 1305. http://dx.doi.org/10.3390/molecules25061305.
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Protein degradation is a fundamental process in all living organisms. An important part of this system is a multisubunit, barrel-shaped protease complex called the proteasome. This enzyme is directly responsible for the proteolysis of ubiquitin- or pup-tagged proteins to smaller peptides. In this study, we present a series of 92 psoralen derivatives, of which 15 displayed inhibitory potency against the Mycobacterium tuberculosis proteasome in low micromolar concentrations. The best inhibitors, i.e., 8, 11, 13 and 15, exhibited a mixed type of inhibition and overall good inhibitory potency in biochemical assays. N-(cyanomethyl)acetamide 8 (Ki = 5.6 µM) and carboxaldehyde-based derivative 15 (Ki = 14.9 µM) were shown to be reversible inhibitors of the enzyme. On the other hand, pyrrolidine-2,5-dione esters 11 and 13 irreversibly inhibited the enzyme with Ki values of 4.2 µM and 1.1 µM, respectively. In addition, we showed that an established immunoproteasome inhibitor, PR-957, is a noncompetitive irreversible inhibitor of the mycobacterial proteasome (Ki = 5.2 ± 1.9 µM, kinact/Ki = 96 ± 41 M−1·s−1). These compounds represent interesting hit compounds for further optimization in the development of new drugs for the treatment of tuberculosis.
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Morgan, Hugh P., Martin J. Walsh, Elizabeth A. Blackburn, Martin A. Wear, Matthew B. Boxer, Min Shen, Henrike Veith i in. "A new family of covalent inhibitors block nucleotide binding to the active site of pyruvate kinase". Biochemical Journal 448, nr 1 (18.10.2012): 67–72. http://dx.doi.org/10.1042/bj20121014.
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PYK (pyruvate kinase) plays a central role in the metabolism of many organisms and cell types, but the elucidation of the details of its function in a systems biology context has been hampered by the lack of specific high-affinity small-molecule inhibitors. High-throughput screening has been used to identify a family of saccharin derivatives which inhibit LmPYK (Leishmania mexicana PYK) activity in a time- (and dose-) dependent manner, a characteristic of irreversible inhibition. The crystal structure of DBS {4-[(1,1-dioxo-1,2-benzothiazol-3-yl)sulfanyl]benzoic acid} complexed with LmPYK shows that the saccharin moiety reacts with an active-site lysine residue (Lys335), forming a covalent bond and sterically hindering the binding of ADP/ATP. Mutation of the lysine residue to an arginine residue eliminated the effect of the inhibitor molecule, providing confirmation of the proposed inhibitor mechanism. This lysine residue is conserved in the active sites of the four human PYK isoenzymes, which were also found to be irreversibly inhibited by DBS. X-ray structures of PYK isoforms show structural differences at the DBS-binding pocket, and this covalent inhibitor of PYK provides a chemical scaffold for the design of new families of potentially isoform-specific irreversible inhibitors.
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Verdugo, Anael, P. K. Vinod, John J. Tyson i Bela Novak. "Molecular mechanisms creating bistable switches at cell cycle transitions". Open Biology 3, nr 3 (marzec 2013): 120179. http://dx.doi.org/10.1098/rsob.120179.
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Progression through the eukaryotic cell cycle is characterized by specific transitions, where cells move irreversibly from stage i −1 of the cycle into stage i . These irreversible cell cycle transitions are regulated by underlying bistable switches, which share some common features. An inhibitory protein stalls progression, and an activatory protein promotes progression. The inhibitor and activator are locked in a double-negative feedback loop, creating a one-way toggle switch that guarantees an irreversible commitment to move forward through the cell cycle, and it opposes regression from stage i to stage i −1. In many cases, the activator is an enzyme that modifies the inhibitor in multiple steps, whereas the hypo-modified inhibitor binds strongly to the activator and resists its enzymatic activity. These interactions are the basis of a reaction motif that provides a simple and generic account of many characteristic properties of cell cycle transitions. To demonstrate this assertion, we apply the motif in detail to the G1/S transition in budding yeast and to the mitotic checkpoint in mammalian cells. Variations of the motif might support irreversible cellular decision-making in other contexts.
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Viczjan, Gabor, Tamas Erdei, Ignac Ovari, Nora Lampe, Reka Szekeres, Mariann Bombicz, Barbara Takacs i in. "A Body of Circumstantial Evidence for the Irreversible Ectonucleotidase Inhibitory Action of FSCPX, an Agent Known as a Selective Irreversible A1 Adenosine Receptor Antagonist So Far". International Journal of Molecular Sciences 22, nr 18 (11.09.2021): 9831. http://dx.doi.org/10.3390/ijms22189831.
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In previous studies using isolated, paced guinea pig left atria, we observed that FSCPX, known as a selective A1 adenosine receptor antagonist, paradoxically increased the direct negative inotropic response to A1 adenosine receptor agonists (determined using concentration/effect (E/c) curves) if NBTI, a nucleoside transport inhibitor, was present. Based on mathematical modeling, we hypothesized that FSCPX blunted the cardiac interstitial adenosine accumulation in response to nucleoside transport blockade, probably by inhibiting CD39 and/or CD73, which are the two main enzymes of the interstitial adenosine production in the heart. The goal of the present study was to test this hypothesis. In vitro CD39 and CD73 inhibitor assays were carried out; furthermore, E/c curves were constructed in isolated, paced rat and guinea pig left atria using adenosine, CHA and CPA (two A1 adenosine receptor agonists), FSCPX, NBTI and NBMPR (two nucleoside transport inhibitors), and PSB-12379 (a CD73 inhibitor), measuring the contractile force. We found that FSCPX did not show any inhibitory effect during the in vitro enzyme assays. However, we successfully reproduced the paradox effect of FSCPX in the rat model, mimicked the “paradox” effect of FSCPX with PSB-12379, and demonstrated the lipophilia of FSCPX, which could explain the negative outcome of inhibitor assays with CD39 and CD73 dissolved in a water-based solution. Taken together, these three pieces of indirect evidence are strong enough to indicate that FSCPX possesses an additional action besides the A1 adenosine receptor antagonism, which action may be the inhibition of an ectonucleotidase. Incidentally, we found that POM-1 inhibited CD73, in addition to CD39.
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Kondža, Martin, Mirza Bojić, Ivona Tomić, Željan Maleš, Valentina Rezić i Ivan Ćavar. "Characterization of the CYP3A4 Enzyme Inhibition Potential of Selected Flavonoids". Molecules 26, nr 10 (19.05.2021): 3018. http://dx.doi.org/10.3390/molecules26103018.
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Acacetin, apigenin, chrysin, and pinocembrin are flavonoid aglycones found in foods such as parsley, honey, celery, and chamomile tea. Flavonoids can act as substrates and inhibitors of the CYP3A4 enzyme, a heme containing enzyme responsible for the metabolism of one third of drugs on the market. The aim of this study was to investigate the inhibitory effect of selected flavonoids on the CYP3A4 enzyme, the kinetics of inhibition, the possible covalent binding of the inhibitor to the enzyme, and whether flavonoids can act as pseudo-irreversible inhibitors. For the determination of inhibition kinetics, nifedipine oxidation was used as a marker reaction. A hemochromopyridine test was used to assess the possible covalent binding to the heme, and incubation with dialysis was used in order to assess the reversibility of the inhibition. All the tested flavonoids inhibited the CYP3A4 enzyme activity. Chrysin was the most potent inhibitor: IC50 = 2.5 ± 0.6 µM, Ki = 2.4 ± 1.0 µM, kinact = 0.07 ± 0.01 min−1, kinact/Ki = 0.03 min−1 µM−1. Chrysin caused the highest reduction of heme (94.5 ± 0.5% residual concentration). None of the tested flavonoids showed pseudo-irreversible inhibition. Although the inactivation of the CYP3A4 enzyme is caused by interaction with heme, inhibitor-heme adducts could not be trapped. These results indicate that flavonoids have the potential to inhibit the CYP3A4 enzyme and interact with other drugs and medications. However, possible food–drug interactions have to be assessed clinically.
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Espín, J. C., i J. Tudela. "Experimental approach to the kinetic study of unstable site-directed irreversible inhibitors: kinetic origin of the apparent positive co-operativity arising from inactivation of trypsin by p-amidinophenylmethanesulphonyl fluoride". Biochemical Journal 299, nr 1 (1.04.1994): 29–35. http://dx.doi.org/10.1042/bj2990029.
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Experimental characterization of enzyme inactivation by unstable irreversible inhibitors has only previously been carried out by using discontinuous methods involving preincubation, removal of samples and further residual activity assays. A continuous method for the kinetic study of these inhibitors in the presence of an auxiliary substrate was recently proposed in a theoretical study. This method was based on approximate expressions for the evolution of the product concentration, which contained series expansions with five or more exponential terms, seriously complicating their use in practice. In the present paper, a new experimental method has been developed for the kinetic study of unstable and site-directed irreversible inhibitors, considering two different ranges of inhibitor concentration. Thus at low inhibitor concentrations, the system evolves from an initial to a final steady state, the rates of which are described by exact analytical equations. At high inhibitor concentrations, however, the product accumulation can be described by an exact uniexponential equation. This simple and efficient method has been applied to the kinetic study of trypsin inactivation by p-amidinophenylmethanesulphonyl fluoride, near the optimum pH of the enzyme. The dependence of the final steady-state rate on the substrate concentration shows apparent positive co-operativity which has not previously been reported. The kinetic origin of this type of co-operativity is predicted by one of the exact analytical equations derived here. The instability of new protein and non-protein irreversible inhibitors has to be carefully characterized to prevent true unstable irreversible inhibitors being wrongly described as allosteric reversible inhibitors.
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Bitonti, A. J., P. J. Casara, P. P. McCann i P. Bey. "Catalytic irreversible inhibition of bacterial and plant arginine decarboxylase activities by novel substrate and product analogues". Biochemical Journal 242, nr 1 (15.02.1987): 69–74. http://dx.doi.org/10.1042/bj2420069.
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Arginine decarboxylase (ADC) activity from Escherichia coli and two plant species (oats and barley) was inhibited by five new substrate (arginine) and product (agmatine) analogues. The five compounds, (E)-alpha-monofluoromethyldehydroarginine (delta-MFMA), alpha-monofluoromethylarginine (MFMA), alpha-monofluoromethylagatine (FMA), alpha-ethynylagmatine (EA) and alpha-allenylagmatine (AA), were all more potent inhibitors of ADC activity than was alpha-difluoromethylarginine (DFMA), the only irreversible inhibitor of this enzyme described previously. The inhibition caused by the five compounds was apparently enzyme-activated and irreversible, since the loss of enzyme activity followed pseudo-first-order kinetics, was time-dependent, the natural substrate of ADC (arginine) blocked the effects of the inhibitors, and the inhibition remained after chromatography of inhibited ADC on Sephadex G-25 or on overnight dialysis of the enzyme. DFMA, FMA, delta-MFMA and MFMA were effective at very low concentrations (10 nM-10 microM) at inhibiting ADC activity in growing E. coli. FMA was also shown to deplete putrescine effectively in E. coli, particularly when combined with an inhibitor of ornithine decarboxylase, alpha-monofluoromethyl-putrescine. The potential uses of the compounds for the study of the role of polyamine biosynthesis in bacteria and plants is discussed.
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Liyanage, Piyumi Dinusha, Pabudi Weerathunge, Mandeep Singh, Vipul Bansal i Rajesh Ramanathan. "L-Cysteine as an Irreversible Inhibitor of the Peroxidase-Mimic Catalytic Activity of 2-Dimensional Ni-Based Nanozymes". Nanomaterials 11, nr 5 (13.05.2021): 1285. http://dx.doi.org/10.3390/nano11051285.
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The ability to modulate the catalytic activity of inorganic nanozymes is of high interest. In particular, understanding the interactions of inhibitor molecules with nanozymes can bring them one step closer to the natural enzymes and has thus started to attract intense interest. To date, a few reversible inhibitors of the nanozyme activity have been reported. However, there are no reports of irreversible inhibitor molecules that can permanently inhibit the activity of nanozymes. In the current work, we show the ability of L-cysteine to act as an irreversible inhibitor to permanently block the nanozyme activity of 2-dimensional (2D) NiO nanosheets. Determination of the steady state kinetic parameters allowed us to obtain mechanistic insights into the catalytic inhibition process. Further, based on the irreversible catalytic inhibition capability of L-cysteine, we demonstrate a highly specific sensor for the detection of this biologically important molecule.
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May, Earl, Daniel Urul, Khanh Huynh, Susan Cornell-Kennon, Venkatesh Nemmara, Zhibing Lu, Samuel Hoare, Michelle Lyles i Erik Schaefer. "Abstract 2061: A proven activity-based workflow for the identification and characterization of time-dependent kinase inhibitors using a continuous assay format". Cancer Research 84, nr 6_Supplement (22.03.2024): 2061. http://dx.doi.org/10.1158/1538-7445.am2024-2061.
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Abstract Time-dependent inhibitors (TDIs) of enzyme targets offer distinct advantages for the development of potent and selective compounds with favorable pharmacokinetic and pharmacodynamic properties. Such inhibitors are characterized by non-linear progress curves: after an initial inhibited velocity, a rate constant governs the transition to a final steady-state reaction rate of the inhibited enzyme. A final rate of zero indicates irreversible inhibition, whereas a non-zero final rate indicates slow-binding inhibition. Characterizing these inhibitory modes of action is enabled with a continuous assay format that avoids the common pitfalls and misleading results seen with end-point assays. A continuous assay format enables efficient and robust determination of the kinetic parameters required to drive structure-activity relationship optimization to streamline the development of more effective drugs. It is important to note that simple IC50s for TDIs will not suffice, and can, indeed, also be misleading. We have developed a robust three-step workflow based on kinetic catalytic activity measurements to quickly identify and characterize TDIs. First, dose-response experiments are conducted with and without an enzyme-inhibitor preincubation step. The curvature of the reaction progress curve in the non-preincubated experiment and a shift in IC50 from the preincubated experiment are indicative of TDI. In the absence of TDI, simple IC50s are reported with, if possible, Ki values. If TDI is present, a second experiment is conducted to assess compound reversibility using either a jump-dilution protocol or a novel free-compound clearance method that uses gel filtration spin columns or spin plates. In either protocol, forward progress curve analysis is used to monitor the recovery of enzymatic activity after dilution of inhibitor in solution. Lastly, the potency of the inhibitor is evaluated using kinetic experiments tailored to the nature of the inhibition – either reversible or irreversible. If reversible, then the rate constant from the reversibility experiment is used to determine the residence time of the molecule. If irreversible, then a 24-point dose-response experiment with serial 1.5-fold dilutions is performed, and all the progress curves are globally fit to determine kinact/KI, and, if possible, kinact and KI separately. The method will be fully described through the characterization of known EGFR inhibitors of three inhibition types: fast-off (Gefitinib), slow binding (Lapatinib), and irreversible (Osimertinib). Citation Format: Earl May, Daniel Urul, Khanh Huynh, Susan Cornell-Kennon, Venkatesh Nemmara, Zhibing Lu, Samuel Hoare, Michelle Lyles, Erik Schaefer. A proven activity-based workflow for the identification and characterization of time-dependent kinase inhibitors using a continuous assay format [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2061.
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Han, Chun, Jiahong Ren, Feng Su, Xiaoqin Hu, Mengyao Li, Zhijun Wang i Lintao Wu. "Hybrids of Quinoline and Anilinopyrimidine: Novel EGFRT790M Inhibitors with Antiproliferative Activity against Non-Small Cell Lung Cancer Cell Lines". Anti-Cancer Agents in Medicinal Chemistry 20, nr 6 (14.06.2020): 724–33. http://dx.doi.org/10.2174/1871520620666200302113206.
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Background: The third-generation irreversible Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors (TKIs) inhibit the T790M mutation while sparing EGFRWT. However, the C797S point mutation confers resistance to existing irreversible EGFRT790M inhibitors. Objective: Novel EGFRT790M inhibitors were designed through hybridization of quinoline and anilinopyrimidine, and biologically evaluated their antiproliferative activity against Non-Small Cell Lung Cancer (NSCLC) cell lines. Methods: The target compounds 11a-h were synthesized and structurally characterized with 1H, 13C Nuclear Magnetic Resonance (NMR) spectroscopy and High-Resolution Mass Spectrometry (HRMS). Their inhibitory effects on tumor cell proliferation and EGFR kinase were biologically evaluated. Additionally, molecular docking studies were also performed on the representative typical EGFRT790M inhibitor. Results: Most of the evaluated compounds displayed moderate antiproliferative activity on H1975 cells with EGFRL858R/T790M. However, compound 11a (IC50 = 2.235 ± 0.565μM) showed stronger inhibition than gefitinib (IC50 = 8.830 ± 0.495μM) in concentration- and time-dependent manner. Moreover, compound 11a exhibited weaker inhibitory activities on cells with EGFRWT. Specifically, compound 11a strongly suppressed EGFRL858R/T790M (IC50 = 0.515 ± 0.011μM) relative to EGFRWT (IC50 = 0.913 ± 0.068μM). Furthermore, molecular docking studies demonstrated its strong binding contacts with the EGFRT790M enzyme through hydrogen bonds and other non-bonded interactions. Conclusion: Taken together, these results indicate that the hybrid of quinoline and anilinopyrimidine 11a, could be a potential inhibitor of EGFRT790M in NSCLC, which warrants further in-depth studies.
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Tikhonova, O. V., V. S. Skvortsov i O. A. Raevsky. "Molecular modeling of acetylcholinesterase interaction with irreversible and reversible organophosphorous inhibitors". Biomeditsinskaya Khimiya 57, nr 1 (styczeń 2011): 61–76. http://dx.doi.org/10.18097/pbmc20115701061.
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Three-dimensional Quantitative Structure-Аctivity Relationship models were designed for irreversible and reversible acetylcholinesterase inhibitors by molecular modeling methods. In case of irreversible inhibitors CoMFA (the comparative analysis of molecular fields) or CoMSIA (the comparative analysis of indexes of molecular similarity) descriptors together with HYBOT 3D fields provide more statistically valid 3D-QSAR models. This indicates importance of donor-acceptor interactions for irreversible acetylcholinesterase inhibition. In case of reversible organophosphorous inhibitors good quality model for structure-activity relationships was developed using CoMFA fields. The obtained models have good predictive power and can be used for estimation of new organophosphorous compounds inhibitor activity that in turn correlates with toxicity of these compounds.
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Poole, R. C., i A. P. Halestrap. "Reversible and irreversible inhibition, by stilbenedisulphonates, of lactate transport into rat erythrocytes. Identification of some new high-affinity inhibitors". Biochemical Journal 275, nr 2 (15.04.1991): 307–12. http://dx.doi.org/10.1042/bj2750307.
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1. Inhibition of L-lactate transport into rat erythrocytes by stilbenedisulphonates was studied under conditions which allowed the contribution of reversible and irreversible inhibition to be assessed. 2. At low temperatures (7 degrees C), 4,4′-di-isothiocyanostilbene-2,2′-disulphonate (DIDS) and other stilbenedisulphonates were found to inhibit lactate transport instantaneously, in a manner which was fully reversible. The most potent reversible inhibitors were 4,4′-dibenzamidostilbene-2,2′-disulphonate (DBDS), DIDS and 4-acetamido-4′isothiocyanostilbene-2,2′-disulphonate (SITS), for which apparent Ki values at 0.5 mM-L-lactate were approx. 36, 53 and 130 microM respectively. 3. DIDS and DBDS were competitive inhibitors with respect to L-lactate, with Ki values of approx 40 microM and 22 microM respectively. 4. After incubation for 1 h at 37 degrees C with DIDS or its dihydro derivative (H2DIDS), which contain the amino-reactive isothiocyanate group, most of the inhibition observed was irreversible. Under these conditions the IC50 value (concn. causing 50% inhibition) for irreversible inhibition by both compounds was approx 100 microM. SITS was much less potent as an irreversible inhibitor of L-lactate transport, approx. 20% inhibition being obtained at 100 microM. 5. The reversible inhibitor DBDS (1 mM) afforded protection against irreversible inhibition by DIDS and H2DIDS (100 microM); protection was 60 and 65% respectively after a 60 min incubation. This indicates that specific binding of the irreversible inhibitors is required before covalent modification can take place. 6. These compounds may be useful high-affinity probes for lactate transport in other tissues and might act as affinity labels for the transport protein(s).
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Yu, Xiangfan, Simei Qiu, Dongshan Sun, Pei Guo i Quhuan Li. "Comparison of Intermolecular Interactions of Irreversible and Reversible Inhibitors with Bruton’s Tyrosine Kinase via Molecular Dynamics Simulations". Molecules 27, nr 21 (2.11.2022): 7451. http://dx.doi.org/10.3390/molecules27217451.
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Bruton’s tyrosine kinase (BTK) is a key protein from the TEC family and is involved in B-cell lymphoma occurrence and development. Targeting BTK is therefore an effective strategy for B-cell lymphoma treatment. Since previous studies on BTK have been limited to structure-function analyses of static protein structures, the dynamics of conformational change of BTK upon inhibitor binding remain unclear. Here, molecular dynamics simulations were conducted to investigate the molecular mechanisms of association and dissociation of a reversible (ARQ531) and irreversible (ibrutinib) small-molecule inhibitor to/from BTK. The results indicated that the BTK kinase domain was found to be locked in an inactive state through local conformational changes in the DFG motif, and P-, A-, and gatekeeper loops. The binding of the inhibitors drove the outward rotation of the C-helix, resulting in the upfolded state of Trp395 and the formation of the salt bridge of Glu445-Arg544, which maintained the inactive conformation state. Met477 and Glu475 in the hinge region were found to be the key residues for inhibitor binding. These findings can be used to evaluate the inhibitory activity of the pharmacophore and applied to the design of effective BTK inhibitors. In addition, the drug resistance to the irreversible inhibitor Ibrutinib was mainly from the strong interaction of Cys481, which was evidenced by the mutational experiment, and further confirmed by the measurement of rupture force and rupture times from steered molecular dynamics simulation. Our results provide mechanistic insights into resistance against BTK-targeting drugs and the key interaction sites for the development of high-quality BTK inhibitors. The steered dynamics simulation also offers a means to rapidly assess the binding capacity of newly designed inhibitors.
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Bastlein, C., i G. Burckhardt. "Sensitivity of rat renal luminal and contraluminal sulfate transport systems to DIDS". American Journal of Physiology-Renal Physiology 250, nr 2 (1.02.1986): F226—F234. http://dx.doi.org/10.1152/ajprenal.1986.250.2.f226.
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4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) was tested as an inhibitor of the sulfate transport systems in rat renal brush border and basolateral membrane vesicles. Na+-driven sulfate uptake into brush border membrane vesicles was half-maximally inhibited at 350 microM DIDS. Proton gradient-driven sulfate uptake into basolateral membrane vesicles was competitively inhibited by DIDS with a Ki of 2.4 microM. The Km for delta pH-driven sulfate uptake was 5.4 microM. The different affinities of the sulfate transport systems for DIDS correlated with different substrate specificities. The luminal transport system accepted a smaller range of anions than the contraluminal system and did not operate as a Na+-independent anion exchanger. After treatment of basolateral membrane vesicles with 50 microM DIDS at pH 8.4 for 30 min, an irreversible inhibition of sulfate uptake was observed. With brush border membranes, only a small irreversible inhibition was obtained. Lack of inhibition after treatment of basolateral membranes with DIDS at pH 6.4 indicated that DIDS reacted with deprotonated amino groups of the transport protein. Sulfate was protected from the irreversible inhibition by DIDS. Sodium-driven uptake of L-glutamate and methylsuccinate into basolateral membrane vesicles was not irreversibly inhibited by DIDS, indicating a specific action of DIDS on the contraluminal sulfate transport system. Irreversible and substrate-protectable inhibition of sulfate transport render DIDS suitable for future affinity labeling studies on the sulfate transport system in basolateral membranes.
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KETTLE, Anthony J., Craig A. GEDYE i Christine C. WINTERBOURN. "Mechanism of inactivation of myeloperoxidase by 4-aminobenzoic acid hydrazide". Biochemical Journal 321, nr 2 (15.01.1997): 503–8. http://dx.doi.org/10.1042/bj3210503.
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Hypochlorous acid is the most powerful oxidant generated by neutrophils and is likely to contribute to the damage mediated by these inflammatory cells. The haem enzyme myeloperoxidase catalyses its production from hydrogen peroxide and chloride. 4-Aminobenzoic acid hydrazide (ABAH) is a potent inhibitor of hypochlorous acid production. In this investigation we show that, in the presence of hydrogen peroxide, ABAH irreversibly inactivates myeloperoxidase. ABAH was oxidized by myeloperoxidase, and kinetic analysis of the inactivation conformed to that for a mechanism-based inhibitor. Inactivation was exacerbated by concentrations of hydrogen peroxide greater than 50 ƁM and by the absence of oxygen. Hydrogen peroxide alone caused minimal inactivation. Reduced glutathione inhibited the oxidation of ABAH as well as the irreversible inhibition of myeloperoxidase. In the presence of oxygen, ABAH and hydrogen peroxide initially converted myeloperoxidase into compound III, which susequently lost haem absorbance. In the absence of oxygen, the enzyme was converted into ferrous myeloperoxidase and its haem groups were rapidly destroyed. We propose that myeloperoxidase oxidizes ABAH to a radical that reduces the enzyme to its ferrous intermediate. Ferrous myeloperoxidase reacts either with oxygen to allow enzyme turnover, or with hydrogen peroxide to give irreversible inactivation.
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Robak, Ewa, i Tadeusz Robak. "Bruton’s Kinase Inhibitors for the Treatment of Immunological Diseases: Current Status and Perspectives". Journal of Clinical Medicine 11, nr 10 (16.05.2022): 2807. http://dx.doi.org/10.3390/jcm11102807.
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The use of Bruton’s tyrosine kinase (BTK) inhibitors has changed the management of patients with B-cell lymphoid malignancies. BTK is an important molecule that interconnects B-cell antigen receptor (BCR) signaling. BTK inhibitors (BTKis) are classified into three categories, namely covalent irreversible inhibitors, covalent reversible inhibitors, and non-covalent reversible inhibitors. Ibrutinib is the first covalent, irreversible BTK inhibitor approved in 2013 as a breakthrough therapy for chronic lymphocytic leukemia patients. Subsequently, two other covalent, irreversible, second-generation BTKis, acalabrutinib and zanubrutinib, have been developed for lymphoid malignancies to reduce the ibrutinib-mediated adverse effects. More recently, irreversible and reversible BTKis have been under development for immune-mediated diseases, including autoimmune hemolytic anemia, immune thrombocytopenia, multiple sclerosis, pemphigus vulgaris, atopic dermatitis, rheumatoid arthritis, systemic lupus erythematosus, Sjögren’s disease, and chronic spontaneous urticaria, among others. This review article summarizes the preclinical and clinical evidence supporting the role of BTKis in various autoimmune, allergic, and inflammatory conditions.
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WILLIAMS, CARVELL H., i BRENDA BELSHAW. "An iodinated, irreversible inhibitor of monoamine oxidase". Biochemical Society Transactions 13, nr 2 (1.04.1985): 469–70. http://dx.doi.org/10.1042/bst0130469.
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Kindler, Hedy L., i Richard L. Schilsky. "Eniluracil: an irreversible inhibitor of dihydropyrimidine dehydrogenase". Expert Opinion on Investigational Drugs 9, nr 7 (lipiec 2000): 1635–49. http://dx.doi.org/10.1517/13543784.9.7.1635.
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Schaschke, Norbert, Dominga Deluca, Irmgard Assfalg-Machleidt, Clara Höhneke, Christian P. Sommerhoff i Werner Machleidt. "Epoxysuccinyl Peptide-Derived Cathepsin B Inhibitors: Modulating Membrane Permeability by Conjugation with the C-Terminal Heptapeptide Segment of Penetratin". Biological Chemistry 383, nr 5 (15.05.2002): 849–52. http://dx.doi.org/10.1515/bc.2002.090.
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Abstract Besides its physiological role in lysosomal protein breakdown, extralysosomal cathepsin B has recently been implicated in apoptotic cell death. Highly specific irreversible cathepsin B inhibitors that are readily cellpermeant should be useful tools to elucidate the effects of cathepsin B in the cytosol. We have covalently functionalised the poorly cellpermeant epoxysuccinyl based cathepsin B inhibitor [RGlyGlyLeu(2S, 3S)tEpsLeuProOH; R=OMe] with the Cterminal heptapeptide segment of penetratin (R=AhxArg ArgNleLysTrpLysLysNH2). The high inhibitory potency and selectivity for cathepsin B versus cathepsin L of the parent compound was not affected by the conjugation with the penetratin heptapeptide. The conjugate was shown to efficiently penetrate into MCF-7 cells as an active inhibitor, thereby circumventing an intracellular activation step that is required by other inhibitors, such as the prodruglike epoxysuccinyl peptides E64d and CA074Me.
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Tipton, K. F., J. M. McCrodden i M. B. Youdim. "Oxidation and enzyme-activated irreversible inhibition of rat liver monoamine oxidase-B by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)". Biochemical Journal 240, nr 2 (1.12.1986): 379–83. http://dx.doi.org/10.1042/bj2400379.
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The compound 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which produces symptoms resembling Parkinson's disease in humans, acts both as a substrate and an enzyme-activated irreversible inhibitor of the B-form of monoamine oxidase from rat liver. Analysis of the inhibitory process showed the compound to be considerably more efficient as a substrate than as an irreversible inhibitor, with about 17000 mol of product being formed per mol of enzyme inactivated. The half-time of the inhibitory process was about 22 min. With the A-form of the enzyme, the compound had a lower Km value and a considerably lower maximum velocity than the corresponding values obtained with the B-form. Under the conditions used in the present work the inhibition of the A-form of the enzyme was largely reversible.
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Greenspan, M. D., H. G. Bull, J. B. Yudkovitz, D. P. Hanf i A. W. Alberts. "Inhibition of 3-hydroxy-3-methylglutaryl-CoA synthase and cholesterol biosynthesis by β-lactone inhibitors and binding of these inhibitors to the enzyme". Biochemical Journal 289, nr 3 (1.02.1993): 889–95. http://dx.doi.org/10.1042/bj2890889.
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The beta-lactones L-659,699 [(E,E)-11-[3-(hydroxymethyl)-4-oxo-2- oxetanyl]-3,5,7-trimethyl-2,4-undecadienoic acid) and its radioactive derivative 3H-L-668,411 (the 2,3-ditritiated methyl ester of L-659,699) inhibited a partially purified preparation of rat liver cytosolic 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase with an IC50 of 0.1 microM. These compounds were also found to inhibit the incorporation of [14C]acetate into sterols in cultured Hep G2 cells with an IC50 of 3 microM. New kinetic evidence indicated that inhibition of the isolated enzyme was irreversible. In contrast, sterol biosynthesis in cultured Hep G2 cells was rapidly restored upon removal of the compound from the medium of inhibited cultures, suggesting reversibility of inhibition in the cells. Radioactivity was found to be associated with a single cytoplasmic protein by SDS/PAGE of the cytoplasm of Hep G2 cells after incubation of the cells with the inhibitor 3H-L-668,411. This protein was identified as cytoplasmic HMG-CoA synthase. Binding of the radioactive compound to the enzyme was decreased with time if the radioactive inhibitor was removed from the medium. Exposure of a gel containing the radioactive enzyme-inhibitor complex to neutral hydroxylamine also resulted in a loss of radioactivity from the gel. The purified rat liver enzyme reacted with the 3H-ligand to form a stable enzyme-inhibitor complex which could be isolated by h.p.l.c. Radioactivity was also subsequently lost from this complex when it was incubated with neutral hydroxylamine. Incorporation of [14C]acetate into cholesterol in mouse liver was inhibited in a reversible manner after oral administration of the beta-lactone inhibitor. These studies, as well as the kinetic evidence presented, suggest that the beta-lactone inhibitors acylate HMG-CoA synthase in a reaction which appears to be irreversible in vitro, but is easily reversed in cultured cells and in animals.
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Robak, Tadeusz, Magda Witkowska i Piotr Smolewski. "The Role of Bruton’s Kinase Inhibitors in Chronic Lymphocytic Leukemia: Current Status and Future Directions". Cancers 14, nr 3 (2.02.2022): 771. http://dx.doi.org/10.3390/cancers14030771.
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The use of Bruton’s tyrosine kinase (BTK) inhibitors has changed the management and clinical history of patients with chronic lymphocytic leukemia (CLL). BTK is a critical molecule that interconnects B-cell antigen receptor (BCR) signaling. BTKis are classified into two categories: irreversible (covalent) inhibitors and reversible (non-covalent) inhibitors. Ibrutinib was the first irreversible BTK inhibitor approved by the U.S. Food and Drug Administration in 2013 as a breakthrough therapy in CLL patients. Subsequently, several studies have evaluated the efficacy and safety of new agents with reduced toxicity when compared with ibrutinib. Two other irreversible, second-generation BTK inhibitors, acalabrutinib and zanubrutinib, were developed to reduce ibrutinib-mediated adverse effects. Additionally, new reversible BTK inhibitors are currently under development in early-phase studies to improve their activity and to diminish adverse effects. This review summarizes the pharmacology, clinical efficacy, safety, dosing, and drug–drug interactions associated with the treatment of CLL with BTK inhibitors and examines their further implications.
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Law, Brian, Daniel Lu, Priyanka Somanath, James T. Palmer, Taisei Kinoshita i Thomas Butler. "Abstract 2665: Irreversible menin inhibitor, BMF-219, inhibits the growth of KRAS-mutated solid tumors". Cancer Research 82, nr 12_Supplement (15.06.2022): 2665. http://dx.doi.org/10.1158/1538-7445.am2022-2665.
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Abstract Introduction: KRAS (Kirsten rat sarcoma virus) is the most frequently mutated isoform amongst RAS oncogenes in human solid tumors being present in a high percentage of colorectal cancers (CRC), non-small cell lung cancers (NSCLC), and pancreatic cancers. With only one approved KRAS G12C inhibitor for NSCLC, KRAS-driven tumors continue to represent a significant unmet medical need where novel effective therapies are highly desired. Menin is a required co-factor of oncogenic transcriptional proteins with functional interactions that are critical for various malignancies including acute leukemia. We previously reported that BMF-219, a novel irreversible menin inhibitor, exhibits strong potency on acute leukemia (MOLM-13) and KRAS-mutant (MiaPaCa-2) cells. Results from MiaPaCa-2 cells prompted our exploration of the effects of BMF-219 in an expanded panel of KRAS-mutant solid tumors through in vitro and ex vivo preclinical models. Methods: BMF-219, clinical reversible menin inhibitors, or clinically approved KRAS G12C inhibitor, sotorasib, were cultured with CRC, NSCLC, pancreatic cancer cell lines for 4-days. Human ex vivo preclinical models harboring KRAS mutations were cultured with BMF-219 and reversible menin for 6-days. Cell viability was measured using CellTiter Glo and IC50 values were calculated. MiaPaCa-2 cells incubated with BMF-219 were analyzed by RNA-seq on the Illumina NextSeq 550 platform. Results: MiaPaCa-2, a KRAS G12C-mutant cell line, showed marked reduction of KRAS expression levels following 24 hours of BMF-219 treatment at 0.5 µM. An expanded panel of 14 CRC, NSCLC and pancreatic KRAS-mutant cell lines harboring G12C, G12D, G12V, and Q61L revealed single-agent BMF-219 activity after a 4-day treatment. Majority of the cell lines tested exhibited >90% inhibition of growth, independent of KRAS mutation type. Sotorasib reached a maximum of 90-93% growth inhibition in three of eight cell lines. By contrast, BMF-219 inhibited cell viability ≥ 90% in six of eight KRAS G12C lung cancer lines. Human CRC, NSCLC and pancreatic ex vivo preclinical models with G12C, G12D, and G12V KRAS mutations were all sensitive to BMF-219 after a 6-day treatment. Complete abrogation of growth was observed in all samples with IC50 values ranging between 0.2 μM - 0.6 μM. Conclusion: KRAS-mutant CRC, NSCLC, pancreatic cancer cell lines and ex vivo preclinical models are highly sensitive to irreversible menin inhibitor, BMF-219, where clinical reversible menin inhibitors displayed limited activity. High potency of BMF-219 was observed amongst various KRAS-mutant cell lines suggesting that BMF-219 broadly inhibits these tumors. As an irreversible menin inhibitor, BMF-219, manifests advantages over the KRAS-targeted inhibitor sotorasib in multiple cell lines tested, and displays unique potency compared with clinical reversible menin inhibitors in ex vivo preclinical models of CRC, NSCLC, and pancreatic cancer. Citation Format: Brian Law, Daniel Lu, Priyanka Somanath, James T. Palmer, Taisei Kinoshita, Thomas Butler. Irreversible menin inhibitor, BMF-219, inhibits the growth of KRAS-mutated solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2665.
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Bridges, A. J. "The Rationale and Strategy Used to Develop a Series of Highly Potent, Irreversible, Inhibitors of the Epidermal Growth Factor Receptor Family of Tyrosine Kinases". Current Medicinal Chemistry 6, nr 9 (wrzesień 1999): 825–43. http://dx.doi.org/10.2174/092986730609220401151141.
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The Epidermal Growth Factor receptor (EGFr) was one of the first oncogenes identified, and it, or its ligands Epidermal Growth Factor (EGF) and Transforming Growth Factor a (TGFa.) are overexpressed in most clinical tumours. As EGF and TGFa. are potent mitogens, it appeared that inhibition of EGFr signaling would be a viable anti-proliferative strategy. Screening found several classes of EGFr inhibitor, one of which, the indolinethiones was developed. The SAR, in common with that of other first generation tyrosine kinase (TK) inhibitors was flat, and potency was poor. Rescreening in presence of a thiol, to remove chemically reactive species, identified only two leads, a pyridopyrimidine and a quinazoline. These were developed into a very broad class of EGFr inhibitors, with great potency and selectivity for EGFr, but poor physicochemical properties, and little if any in vivo anti-tumour activity. Meanwhile the complex role of other members of the EGFr TK family in oncogenesis, was becoming apparent, suggesting that the whole EGFr family should be inhibited. The difficulty of finding potent compounds with acceptable pharmacokinetics also suggested that irreversible inhibitors of the TK might produce better in vivo profiles. Modeling suggested that the unusual Cys773 residue might be reached from the 6/7-positions of quinazoline and pyridopyrimidine inhibitors. Inhibitors with acrylamides at these positions proved to be irreversible alkylating agents for both EGFr and erbB-2 with cellular inhibitory activities in the low nanomolar range, and very potent in vivo• antitumour activity. Optimized inhibitors had exceptionally potent oral antitumour activity, with negligible cytotoxicity.
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Hashimoto, Yoshitami, i Hirofumi Tanaka. "Mre11 exonuclease activity promotes irreversible mitotic progression under replication stress". Life Science Alliance 5, nr 6 (15.03.2022): e202101249. http://dx.doi.org/10.26508/lsa.202101249.
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Mre11 is a versatile exo-/endonuclease involved in multiple aspects of DNA replication and repair, such as DSB end processing and checkpoint activation. We previously demonstrated that forced mitotic entry drives replisome disassembly at stalled replication forks in Xenopus egg extracts. Here, we examined the effects of various chemical inhibitors using this system and discovered a novel role of Mre11 exonuclease activity in promoting mitotic entry under replication stress. Mre11 activity was necessary for the initial progression of mitotic entry in the presence of stalled forks but unnecessary in the absence of stalled forks or after mitotic entry. In the absence of Mre11 activity, mitotic CDK was inactivated by Wee1/Myt1–dependent phosphorylation, causing mitotic exit. An inhibitor of Wee1/Myt1 or a nonphosphorylatable CDK1 mutant was able to partially bypass the requirement of Mre11 for mitotic entry. These results suggest that Mre11 exonuclease activity facilitates the processing of stalled replication forks upon mitotic entry, which attenuates the inhibitory pathways of mitotic CDK activation, leading to irreversible mitotic progression and replisome disassembly.
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Nakatani, Toshiyuki, Ken Uda, Takeshi Yamaura, Masaru Takasaki, Akimi Akashi, Fangli Chen, Yuichi Ishikawa i in. "Development of FF-10101, a Novel Irreversible FLT3 Inhibitor, Which Overcomes Drug Resistance Mutations". Blood 126, nr 23 (3.12.2015): 1353. http://dx.doi.org/10.1182/blood.v126.23.1353.1353.
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Abstract Background: FLT3 is one of the most frequently mutated genes in acute myeloid leukemia (AML). Internal tandem duplication (ITD) of juxtamembrane domain sequence and missense point mutations at D835 residue within kinase domain are major mutations of FLT3 in AML. These mutations induce constitutive activation of FLT3 and its downstream pathway, resulting in aberrant cell proliferation of AML cells. FLT3 is, therefore, believed to be an attractive drug target for AML. Several FLT3 inhibitors were evaluated in clinical trials and they demonstrated clinical efficacy; however, drug-resistant secondary mutations such as F691L and D835 mutations with FLT3-ITD were often appeared. Therefore development of novel FLT3 inhibitors is required to overcome resistance to current FLT3 inhibitors. Here we report that a novel irreversible FLT3 inhibitor, FF-10101 is a promising agent for AML therapy. Methods: Bone marrow samples from patients with AML were subjected to Ficoll-Hypaque density gradient centrifugation. Informed consent was obtained from all patients, and approval was obtained from the ethics committee of our institute. In vitro growth inhibitory assay was performed with leukemia cell lines and 32D transfectants in liquid culture and primary AML cells in semisolid culture. Cell viability was determined by MTS assay or ATP quantification assay. For in vivo efficacy study, leukemia xenograft mouse model was prepared by tale vein injection of MOLM-13 cells or primary AML cells. Efficacies of tested compounds were evaluated by detection of human CD45-positive cells in bone marrow cells obtained from femurs at the end of studies. Results: Kinase profiling assay with 216 human recombinant kinases revealed that FF-10101 selectively and potently inhibited kinase activities of wtFLT3 and FLT3 D835Y with IC50 values of 0.20 nM and 0.16 nM, respectively. In MV4-11 cells, FF-10101 treatment decreased phosphorylation of FLT3 and its downstream molecules in a dose-dependent manner. FF-10101 treatment for 2 days demonstrated growth inhibitory effect on FLT3-dependent human cell lines, MV4-11, MOLM-13, MOLM-14 and 32D transfectants expressing FLT3-ITD with equal to or greater potency than Quizartinib, a highly potent FLT3 inhibitor currently under clinical development for AML (FF-10101 IC50=0.83 nM-2.4 nM, Quizartinib IC50=0.95 nM-4.5 nM). Cell cycle arrest was observed followed by increased sub-G1 population in MV4-11 cells treated with 1 nM FF-10101. Importantly, FF-10101 retained growth inhibitory activities against 32D transfectants expressing drug resistance mutations such as FLT3-ITD/D835Y, FLT3-ITD/Y842C or FLT3-ITD/Y842H with IC50 values of 0.66-3.1 nM, although Quizartinib demonstrated weak inhibitory effects with IC50 values of 85-150nM. In mice xenografted with MOLM-13, oral administration of 5 mg/kg FF-10101 once daily for 8 days significantly decreased MOLM-13 cells in bone marrow as compared to vehicle administration (p<0.001). Next, anti-leukemic effect of FF-10101 was assessed by using primary AML cells. In vitro cell growth assay, 1 week treatment of FF-10101 significantly reduced primary AML cells harboring FLT3-ITD. Growth inhibitory effect was also observed in primary AML cells harboring FLT3 D835H mutation, although Quizartinib had little effect. When 10 mg/kg FF-10101 was orally administrated twice daily to mice xenografted with primary AML cells with FLT3-ITD, AML cells in bone marrow were significantly reduced with comparable efficacy of Quizartinib. Furthermore, FF-10101 demonstrated more potent efficacy than Quizartinib in mice xenografted with primary AML cells harboring FLT3 D835H mutation. FF-10101 also retained its efficacy against mice xenografted with residual AML cells in Quizartinib-treated mice inoculated with primary AML cells harboring FLT3 D835H. Conclusions: We have developed a novel irreversible FLT3 inhibitor, FF-10101. FF-10101 showed potent anti-leukemic effect on cell lines and primary AML cells by selective inhibition of FLT3 both in vitro and in vivo. Notably, FF-10101 also has potency against drug resistance mutations. These results strongly indicate that FF-10101 is a promising agent for AML patients with FLT3 mutations. Phase I study of FF-10101 for AML patients is planned for 2016. Disclosures Nakatani: FUJIFILM Corporation: Employment. Uda:FUJIFILM Corporation: Employment. Yamaura:FUJIFILM Corporation: Employment. Takasaki:FUJIFILM Corporation: Employment. Ishikawa:GlaxoSmithKline K.K.: Research Funding. Hagiwara:FUJIFILM Corporation: Employment. Kiyoi:Eisai Co., Ltd.: Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding; Pfizer Inc.: Research Funding; Yakult Honsha Co.,Ltd.: Research Funding; Alexion Pharmaceuticals: Research Funding; MSD K.K.: Research Funding; Taisho Toyama Pharmaceutical Co., Ltd.: Research Funding; Teijin Ltd.: Research Funding; Novartis Pharma K.K.: Research Funding; Mochida Pharmaceutical Co., Ltd.: Research Funding; Astellas Pharma Inc.: Consultancy, Research Funding; Japan Blood Products Organization: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; FUJIFILM RI Pharma Co.,Ltd.: Research Funding; Nippon Boehringer Ingelheim Co., Ltd.: Research Funding; FUJIFILM Corporation: Patents & Royalties, Research Funding; Zenyaku Kogyo Co., Ltd.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding. Naoe:FUJIFILM Corporation: Patents & Royalties, Research Funding; Celgene K.K.: Research Funding; Pfizer Inc.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Patents & Royalties, Research Funding; Chugai Pharmaceutical Co., Ltd.: Patents & Royalties; Toyama Chemical CO., LTD.: Research Funding; Nippon Boehringer Ingelheim Co., Ltd.: Research Funding; Astellas Pharma Inc.: Research Funding.
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Boudier, C., i J. G. Bieth. "Oxidized mucus proteinase inhibitor: a fairly potent neutrophil elastase inhibitor". Biochemical Journal 303, nr 1 (1.10.1994): 61–68. http://dx.doi.org/10.1042/bj3030061.
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N-chlorosuccinimide oxidizes one of the methionine residues of mucus proteinase inhibitor with a second-order rate constant of 1.5 M-1.s-1. Cyanogen bromide cleavage and NH2-terminal sequencing show that the modified residue is methionine-73, the P′1 component of the inhibitor's active centre. Oxidation of the inhibitor decreases its neutrophil elastase inhibitory capacity but does not fully abolish it. The kinetic parameters describing the elastase-oxidized inhibitor interaction are: association rate constant kass. = 2.6 x 10(5) M-1.s-1, dissociation rate constant kdiss. = 2.9 x 10(-3) s-1 and equilibrium dissociation constant Ki = 1.1 x 10(-8) M. Comparison with the native inhibitor indicates that oxidation decreases kass. by a factor of 18.8 and increases kdiss. by a factor of 6.4, and therefore leads to a 120-fold increase in Ki. Yet, the oxidized inhibitor may still act as a potent elastase inhibitor in the upper respiratory tract where its concentration is 500-fold higher than Ki, i.e. where the elastase inhibition is pseudo-irreversible. Experiments in vitro with fibrous human lung elastin, the most important natural substrate of elastase, support this view: 1.35 microM elastase is fully inhibited by 5-6 microM oxidized inhibitor whether the enzyme-inhibitor complex is formed in the presence or absence of elastin and whether elastase is pre-adsorbed on elastin or not.
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Lombardi, Paolo. "The Irreversible Inhibition of Aromatase (Oestrogen Synthetase) by Steroidal Compounds". Current Pharmaceutical Design 1, nr 1 (czerwiec 1995): 23–50. http://dx.doi.org/10.2174/1381612801666220524190226.
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Approximately one-third of the over 100,000 annual new breast carcinoma cases in the USA are classified as hormone-dependent. In patients with hormone-responsive neoplasms, the withdrawal of oestrogens or the alteration of oestrogens action result in tumour regression. In the last three decades clinical investigation has focused on the inhibition of oestrogen biosynthesis, since aromatase (oestrogen synthetase) is the rate-limiting enzyme in the conversion of androgens to oestrogens. More recently, aromatase became the target enzyme of specifically designed, mechanism-activated inhibitors. Such compounds should have high affinity for the enzyme, longer duration of pharmacological action, since their inactivation results by a covalent binding of the .inhibitor to the enzyme, and consequently they should show reduced toxicity with respect to both hormonal and non- . hormonal agents currently clinically available. 4-Hydroxyandrost-4-ene-3,17-dione (3), the first potent ' mechanism-based inhibitor identified, entered the market in 1993. A variety of promising compounds are currently following in advanced clinical trials. This review will update efforts toward the discovery and the synthesis of mechanism-based steroidal inhibitors of aromatase, with emphasis on those with proven efficacy in the animal, and with particular relevance to those which appeared solely in the patent literature.
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Gantt, Soren M., Joon Mo Myung, Marcelo R. S. Briones, Wei Dong Li, E. J. Corey, Satoshi Omura, Victor Nussenzweig i Photini Sinnis. "Proteasome Inhibitors Block Development ofPlasmodium spp". Antimicrobial Agents and Chemotherapy 42, nr 10 (1.10.1998): 2731–38. http://dx.doi.org/10.1128/aac.42.10.2731.
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ABSTRACT Proteasomes degrade most of the proteins inside eukaryotic cells, including transcription factors and regulators of cell cycle progression. Here we show that nanomolar concentrations of lactacystin, a specific irreversible inhibitor of the 20S proteasome, inhibit development of the exoerythrocytic and erythrocytic stages of the malaria parasite. Although lactacystin-treated Plasmodium berghei sporozoites are still invasive, their development into exoerythrocytic forms (EEF) is inhibited in vitro and in vivo. Erythrocytic schizogony of P. falciparum in vitro is also profoundly inhibited when drug treatment of the synchronized parasites is prior, but not subsequent, to the initiation of DNA synthesis, suggesting that the inhibitory effect of lactacystin is cell cycle specific. Lactacystin reduces P. berghei parasitemia in rats, but the therapeutic index is very low. Along with other studies showing that lactacystin inhibits stage-specific transformation inTrypanosoma and Entamoeba spp., these findings highlight the potential of proteasome inhibitors as drugs for the treatment of diseases caused by protozoan parasites.
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Zeng, Qingbei, Anilkumar G. Nair, Stuart B. Rosenblum, Hsueh-Cheng Huang, Charles A. Lesburg, Yueheng Jiang, Oleg Selyutin i in. "Discovery of an irreversible HCV NS5B polymerase inhibitor". Bioorganic & Medicinal Chemistry Letters 23, nr 24 (grudzień 2013): 6585–87. http://dx.doi.org/10.1016/j.bmcl.2013.10.060.
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Lawyer, Arthur L., Sarita R. Kelley i Judith I. Allen. "Use of Pyruvate-Phosphate Dikinase as a Target for Herbicide Design: Analysis of Inhibitor Specificity". Zeitschrift für Naturforschung C 42, nr 6 (1.06.1987): 834–36. http://dx.doi.org/10.1515/znc-1987-0633.
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Pyruvate-phosphate dikinase (PPDK) was targeted for inhibitor design because of its central role in C4-type photosynthetic carbon metabolism and its relative absence in C3-type plants and organisms of the animal kingdom. Compounds were tested for their activities as reversible and irreversible inhibitors of PPDK isolated from maize. The relative activity of the test compounds against phosphoenolpvruvate carboxylase (PEPCase), isolated from wheat, was used as a measure of the specificity of the inhibitors for the targeted enzyme. PPDK. An ideal compound for successful herbicide design should be an inhibitor which is specific toward the targeted enzyme and either effectively inhibits enzyme activity at very low concentrations or inactivates the enzyme through an irreversible mechanism. Using results obtained with commercially purchased compounds. the discussion will emphasize the difficulty of obtaining specific inhibitors toward PPDK. Another report from this laboratory (A. L. Lawyer. S. R. Kelley, and J. I. Allen, in: Proc. Seventh Internat. Congr. Photosynth. (.I. Biggins, ed.). in press) emphasizes other results obtained from the targeting of PPDK for herbicide activity.
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Lawyer, Arthur L., Sarita R. Kelley i Judith I. Allen. "Use of Pyruvate-Phosphate Dikinase as a Target for Herbicide Design: Analysis of Inhibitor Specificity". Zeitschrift für Naturforschung C 42, nr 7-8 (1.08.1987): 834–36. http://dx.doi.org/10.1515/znc-1987-7-816.
Pełny tekst źródłaStreszczenie:
Pyruvate-phosphate dikinase (PPDK) was targeted for inhibitor design because of its central role in C4-type photosynthetic carbon metabolism and its relative absence in C3-type plants and organisms of the animal kingdom. Compounds were tested for their activities as reversible and irreversible inhibitors of PPDK isolated from maize. The relative activity of the test compounds against phosphoenolpvruvate carboxylase (PEPCase), isolated from wheat, was used as a measure of the specificity of the inhibitors for the targeted enzyme. PPDK. An ideal compound for successful herbicide design should be an inhibitor which is specific toward the targeted enzyme and either effectively inhibits enzyme activity at very low concentrations or inactivates the enzyme through an irreversible mechanism. Using results obtained with commercially purchased compounds. the discussion will emphasize the difficulty of obtaining specific inhibitors toward PPDK. Another report from this laboratory (A. L. Lawyer. S. R. Kelley, and J. I. Allen, in: Proc. Seventh Internat. Congr. Photosynth. (J. Biggins, ed.), in press) emphasizes other results obtained from the targeting of PPDK for herbicide activity.
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Barrand, M. A., i B. A. Callingham. "The interaction of hydralazine with a semicarbazide-sensitive amine oxidase in brown adipose tissue of the rat. Its use as a radioactive ligand for the enzyme". Biochemical Journal 232, nr 2 (1.12.1985): 415–23. http://dx.doi.org/10.1042/bj2320415.
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Hydralazine is a potent irreversible inhibitor of the semicarbazide-sensitive amine oxidase (SSAO) found in brown fat. Initially it may act on the enzyme as a competitive inhibitor, but irreversible inhibition occurs rapidly in a concentration- and temperature-dependent manner. The presence of primary amines known to be substrates for the enzyme, but not of secondary amines, which are not metabolized by SSAO, diminishes this rate of inactivation, whereas removal of O2 is without effect. The kinetic pattern of inactivation of SSAO by hydralazine is consistent with an active-site-directed site-saturable binding followed by the development of an irreversible enzyme-inhibitor complex. [3H]Hydralazine, used as an affinity label for SSAO, shows saturable binding to brown-fat membranes. This binding is inhibited by other inhibitors of SSAO. The rate of binding to membrane pellets containing SSAO is not affected by substrates for the enzyme. However, if solubilized partially purified SSAO preparations are used instead, the rate of binding is lowered in the presence of the SSAO substrate benzylamine. 3H-labelled material solubilized from [3H]hydralazine-treated membrane pellets by Triton X-100 at that detergent/protein ratio which releases SSAO from membranes shows the same gel-filtration characteristics as SSAO and appears by lentil lectin-agarose affinity chromatography to contain similar carbohydrate moieties. 3H-labelled material, partially purified by gel filtration and affinity chromatography, produces predominantly a single band of radioactivity on sodium dodecyl sulphate/polyacrylamide-gel electrophoresis. The position of this band corresponds to an Mr of about 94 000, almost exactly half the Mr already estimated for the functional unit of SSAO. Radiolabelled hydralazine may thus be used as a label for purified SSAO, but it is not specific enough to be suitable as a ligand in vivo.
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Maryška, Michal, Lucie Svobodová, Wim Dehaen, Martina Hrabinová, Michaela Rumlová, Ondřej Soukup i Martin Kuchař. "Heterocyclic Cathinones as Inhibitors of Kynurenine Aminotransferase II—Design, Synthesis, and Evaluation". Pharmaceuticals 14, nr 12 (10.12.2021): 1291. http://dx.doi.org/10.3390/ph14121291.
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Kynurenic acid is a neuroprotective metabolite of tryptophan formed by kynurenine aminotransferase (KAT) catalyzed transformation of kynurenine. However, its high brain levels are associated with cognitive deficit and with the pathophysiology of schizophrenia. Although several classes of KAT inhibitors have been published, the search for new inhibitor chemotypes is crucial for the process of finding suitable clinical candidates. Therefore, we used pharmacophore modeling and molecular docking, which predicted derivatives of heterocyclic amino ketones as new potential irreversible inhibitors of kynurenine aminotransferase II. Thiazole and triazole-based amino ketones were synthesized within a SAR study and their inhibitory activities were evaluated in vitro. The observed activities confirmed our computational model and, moreover, the best compounds showed sub-micromolar inhibitory activity with 2-alaninoyl-5-(4-fluorophenyl)thiazole having IC50 = 0.097 µM.
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Zhang, Datong, He Gong i Fancui Meng. "Recent Advances in BTK Inhibitors for the Treatment of Inflammatory and Autoimmune Diseases". Molecules 26, nr 16 (13.08.2021): 4907. http://dx.doi.org/10.3390/molecules26164907.
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Bruton’s tyrosine kinase (BTK) plays a crucial role in B-cell receptor and Fc receptor signaling pathways. BTK is also involved in the regulation of Toll-like receptors and chemokine receptors. Given the central role of BTK in immunity, BTK inhibition represents a promising therapeutic approach for the treatment of inflammatory and autoimmune diseases. Great efforts have been made in developing BTK inhibitors for potential clinical applications in inflammatory and autoimmune diseases. This review covers the recent development of BTK inhibitors at preclinical and clinical stages in treating these diseases. Individual examples of three types of inhibitors, namely covalent irreversible inhibitors, covalent reversible inhibitors, and non-covalent reversible inhibitors, are discussed with a focus on their structure, bioactivity and selectivity. Contrary to expectations, reversible BTK inhibitors have not yielded a significant breakthrough so far. The development of covalent, irreversible BTK inhibitors has progressed more rapidly. Many candidates entered different stages of clinical trials; tolebrutinib and evobrutinib are undergoing phase 3 clinical evaluation. Rilzabrutinib, a covalent reversible BTK inhibitor, is now in phase 3 clinical trials and also offers a promising future. An analysis of the protein–inhibitor interactions based on published co-crystal structures provides useful clues for the rational design of safe and effective small-molecule BTK inhibitors.
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Hopkins, Michael, John J. Tyson i Béla Novák. "Cell-cycle transitions: a common role for stoichiometric inhibitors". Molecular Biology of the Cell 28, nr 23 (7.11.2017): 3437–46. http://dx.doi.org/10.1091/mbc.e17-06-0349.
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The cell division cycle is the process by which eukaryotic cells replicate their chromosomes and partition them to two daughter cells. To maintain the integrity of the genome, proliferating cells must be able to block progression through the division cycle at key transition points (called “checkpoints”) if there have been problems in the replication of the chromosomes or their biorientation on the mitotic spindle. These checkpoints are governed by protein-interaction networks, composed of phase-specific cell-cycle activators and inhibitors. Examples include Cdk1:Clb5 and its inhibitor Sic1 at the G1/S checkpoint in budding yeast, APC:Cdc20 and its inhibitor MCC at the mitotic checkpoint, and PP2A:B55 and its inhibitor, alpha-endosulfine, at the mitotic-exit checkpoint. Each of these inhibitors is a substrate as well as a stoichiometric inhibitor of the cell-cycle activator. Because the production of each inhibitor is promoted by a regulatory protein that is itself inhibited by the cell-cycle activator, their interaction network presents a regulatory motif characteristic of a “feedback-amplified domineering substrate” (FADS). We describe how the FADS motif responds to signals in the manner of a bistable toggle switch, and then we discuss how this toggle switch accounts for the abrupt and irreversible nature of three specific cell-cycle checkpoints.
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Lee, Eun, Hyewon Cho, Da Kyung Lee, JuHyun Ha, Byeong Jo Choi, Ji Hye Jeong, Jae-Ha Ryu, Jong Soon Kang i Raok Jeon. "Discovery of 5-Phenoxy-2-aminopyridine Derivatives as Potent and Selective Irreversible Inhibitors of Bruton’s Tyrosine Kinase". International Journal of Molecular Sciences 21, nr 21 (28.10.2020): 8006. http://dx.doi.org/10.3390/ijms21218006.
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As a member of the tyrosine protein kinase Tec (TEC) family, Bruton’s tyrosine kinase (BTK) is considered a promising therapeutic target due to its crucial roles in the B cell receptor (BCR) signaling pathway. Although many types of BTK inhibitors have been reported, there is an unmet need to achieve selective BTK inhibitors to reduce side effects. To obtain BTK selectivity and efficacy, we designed a novel series of type II BTK inhibitors which can occupy the allosteric pocket induced by the DFG-out conformation and introduced an electrophilic warhead for targeting Cys481. In this article, we have described the structure–activity relationships (SARs) leading to a novel series of potent and selective piperazine and tetrahydroisoquinoline linked 5-phenoxy-2-aminopyridine irreversible inhibitors of BTK. Compound 18g showed good potency and selectivity, and its biological activity was evaluated in hematological tumor cell lines. The in vivo efficacy of 18g was also tested in a Raji xenograft mouse model, and it significantly reduced tumor size, with 46.8% inhibition compared with vehicle. Therefore, we have presented the novel, potent, and selective irreversible inhibitor 18g as a type II BTK inhibitor.
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Brullo, Chiara, Carla Villa, Bruno Tasso, Eleonora Russo i Andrea Spallarossa. "Btk Inhibitors: A Medicinal Chemistry and Drug Delivery Perspective". International Journal of Molecular Sciences 22, nr 14 (16.07.2021): 7641. http://dx.doi.org/10.3390/ijms22147641.
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In the past few years, Bruton’s tyrosine Kinase (Btk) has emerged as new target in medicinal chemistry. Since approval of ibrutinib in 2013 for treatment of different hematological cancers (as leukemias and lymphomas), two other irreversible Btk inhibitors have been launched on the market. In the attempt to overcome irreversible Btk inhibitor limitations, reversible compounds have been developed and are currently under evaluation. In recent years, many Btk inhibitors have been patented and reported in the literature. In this review, we summarized the (ir)reversible Btk inhibitors recently developed and studied clinical trials and preclinical investigations for malignancies, chronic inflammation conditions and SARS-CoV-2 infection, covering advances in the field of medicinal chemistry. Furthermore, the nanoformulations studied to increase ibrutinib bioavailability are reported.
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He, Ran, Kyoungsook Park, Hongyi Cai, Arun Kapoor, Michael Forman, Bryan Mott, Gary H. Posner i Ravit Arav-Boger. "Artemisinin-Derived Dimer Diphenyl Phosphate Is an Irreversible Inhibitor of Human Cytomegalovirus Replication". Antimicrobial Agents and Chemotherapy 56, nr 7 (30.04.2012): 3508–15. http://dx.doi.org/10.1128/aac.00519-12.
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ABSTRACTWe previously reported that among a series of artemisinin-derived monomers and dimers, dimer diphenyl phosphate (838) was the most potent inhibitor of human cytomegalovirus (CMV) replication. Our continued investigation of a prototypic artemisinin monomer (artesunate [AS]) and dimer (838) now reveals that both compounds have specific activity against CMV but do not inhibit lytic replication of human herpesvirus 1 or 2 or Epstein-Barr virus. AS and 838 inhibited CMV replication during the first 24 h of the virus replication cycle, earlier than the time of ganciclovir (GCV) activities and prior to DNA synthesis. Neither compound inhibited virus entry. Quantification of DNA replication and virus yield revealed a similar level of inhibition by GCV, but AS and 838 had a 10-fold-higher inhibition of virus yield than of DNA replication, suggesting that artemisinins could inhibit CMV through multiple steps: a predominant early inhibition and possibly an additional step following DNA replication. During the strong early CMV inhibition, the transcription of immediate-early genes was not significantly downregulated, and viral protein expression was reduced only after 48 h. AS and GCV were reversible CMV inhibitors, but the inhibition of CMV replication by 838 was irreversible. Combinations of GCV and 838 as well as GCV and AS were highly synergistic. Finally, treatment with 838, but not AS, prior to CMV infection demonstrated strong anti-CMV activity. These findings illustrate the unique activities of dimer 838, including early and irreversible CMV inhibition, possibly by tight binding to its target.
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Penning, T. M. "Irreversible inhibition of Δ5-3-oxosteroid isomerase by 2-substituted progesterones". Biochemical Journal 226, nr 2 (1.03.1985): 469–76. http://dx.doi.org/10.1042/bj2260469.
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2 alpha-Cyanoprogesterone (I) and 2-hydroxymethyleneprogesterone (II) were synthesized and screened as irreversible active-site-directed inhibitors of the delta 5-3-oxosteroid isomerase (EC 5.3.3.1) from Pseudomonas testosteroni. Both compounds were found to inhibit the purified bacterial enzyme in a time-dependent manner. In either case the inactivated enzyme could be dialysed without return of activity, indicating that a stable covalent bond had formed between the inhibitor and the enzyme. Inactivation mediated by compounds (I) and (II) followed pseudo-first-order kinetics, and at higher inhibitor concentrations saturation was observed. The competitive inhibitor 17 beta-oestradiol offered protection against the inactivation mediated by both compounds, and initial-rate studies indicated that compounds (I) and (II) can also act as competitive inhibitors yielding Ki values identical with those generated during inactivation experiments. 2 alpha-Cyanoprogesterone (I) and 2-hydroxymethyleneprogesterone (II) thus appear to be active-site-directed. To compare the reactivity of these 2-substituted progesterones with other irreversible inhibitors of the isomerase, 3 beta-spiro-oxiranyl-5 alpha-pregnan-20 beta-ol (III) was synthesized as the C21 analogue of 3 beta-spiro-oxiranyl-5 alpha-androstan-17 beta-ol, which is a potent inactivator of the isomerase [Pollack, Kayser & Bevins (1979) Biochem. Biophys. Res. Commun. 91, 783-790]. Comparison of the bimolecular rate constants for inactivation (k+3/Ki) mediated by compounds (I)-(III) indicated the following order of reactivity: (III) greater than (II) greater than (I). 2-Mercaptoethanol offers complete protection against the inactivation of the isomerase mediated by 2 alpha-cyanoprogesterone (I). Under the conditions of inactivation compound (I) appears to be completely stable, and no evidence could be obtained for enolate ion formation in the presence or absence of enzyme. It is suggested that cyanoprogesterone inactivates the isomerase after direct nucleophilic attack at the electropositive 2-position, and that tautomerization plays no role in the inactivation event. By contrast, 2-mercaptoethanol offers no protection against the inactivation mediated by 2-hydroxymethyleneprogesterone, and under the conditions of inactivation this compound appears to exist in the semi-enolized form.
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Park, Jong-Hyun, Yeon Ha Ju, Ji Won Choi, Hyo Jung Song, Bo Ko Jang, Junsung Woo, Heejung Chun i in. "Newly developed reversible MAO-B inhibitor circumvents the shortcomings of irreversible inhibitors in Alzheimer’s disease". Science Advances 5, nr 3 (marzec 2019): eaav0316. http://dx.doi.org/10.1126/sciadv.aav0316.
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Monoamine oxidase–B (MAO-B) has recently emerged as a potential therapeutic target for Alzheimer’s disease (AD) because of its association with aberrant γ-aminobutyric acid (GABA) production in reactive astrocytes. Although short-term treatment with irreversible MAO-B inhibitors, such as selegiline, improves cognitive deficits in AD patients, long-term treatments have shown disappointing results. We show that prolonged treatment with selegiline fails to reduce aberrant astrocytic GABA levels and rescue memory impairment in APP/PS1 mice, an animal model of AD, because of increased activity in compensatory genes for a GABA-synthesizing enzyme, diamine oxidase (DAO). We have developed a potent, highly selective, and reversible MAO-B inhibitor, KDS2010 (IC50= 7.6 nM; 12,500-fold selectivity over MAO-A), which overcomes the disadvantages of the irreversible MAO-B inhibitor. Long-term treatment with KDS2010 does not induce compensatory mechanisms, thereby significantly attenuating increased astrocytic GABA levels and astrogliosis, enhancing synaptic transmission, and rescuing learning and memory impairments in APP/PS1 mice.
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Steverding, Dietmar. "On the Reversible and Irreversible Inhibition of Rhodesain by Curcumin". Molecules 25, nr 1 (30.12.2019): 143. http://dx.doi.org/10.3390/molecules25010143.
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Previously, it was suggested that the natural compound curcumin is an irreversible inhibitor of rhodesain, the major lysosomal cysteine protease of the protozoan parasite Trypanosoma brucei. The suggestion was based on a time-dependent inhibition of the enzyme by curcumin and a lack of recovery of activity of the enzyme after pre-incubation with curcumin. This study provides clear evidence that curcumin is a reversible, non-competitive inhibitor of rhodesain. In addition, the study also shows that the apparent irreversible inhibition of curcumin is only observed when no thiol-reducing reagent is included in the measuring buffer and insufficient solubilising agent is added to fully dissolve curcumin in the aqueous solution. Thus, the previous observation that curcumin acts as an irreversible inhibitor for rhodesain was based on a misinterpretation of experimental findings.
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Lighezan, Rodica, Adrian Sturza, Oana M. Duicu, Raluca A. Ceausu, Adrian Vaduva, Marian Gaspar, Horea Feier i in. "Monoamine oxidase inhibition improves vascular function in mammary arteries from nondiabetic and diabetic patients with coronary heart disease". Canadian Journal of Physiology and Pharmacology 94, nr 10 (październik 2016): 1040–47. http://dx.doi.org/10.1139/cjpp-2015-0580.
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Monoamine oxidases (MAOs) are mitochondrial enzymes with 2 isoforms that have emerged as important contributors to cardiovascular oxidative stress via the constant generation of hydrogen peroxide. The present study was purported to assess whether MAO-derived H2O2 contributes to the endothelial dysfunction in mammary arteries harvested from coronary heart disease patients with and without diabetes mellitus subjected to coronary artery bypass grafting. To this aim, the effects of MAO inhibition on vascular contractility to phenylephrine and endothelial-dependent relaxation (EDR) in response to acetylcholine were studied in vascular segments. Clorgyline (irreversible MAO-A inhibitor), selegiline (irreversible MAO-B inhibitor), and moclobemide (reversible MAO-A inhibitor) were applied in the organ bath (10 μmol/L). MAO expression was assessed by immunohistochemistry. We found a constant impairment of EDR that has been significantly attenuated in the presence of the MAO-A and MAO-B inhibitors in both groups of coronary heart disease patients. MAO-B was the dominant isoform in all human diseased vessels. In conclusion, in vitro inhibition of MAO significantly improved EDR in human mammary arteries, regardless of the presence of diabetes. These data suggest that MAO inhibitors might be useful in restoring endothelial response in clinical conditions associated with increased oxidative stress, such as coronary artery disease and diabetes.
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Schröder, Martin, Panagis Filippakopoulos, Martin P. Schwalm, Carla A. Ferrer, David H. Drewry, Stefan Knapp i Apirat Chaikuad. "Crystal Structure and Inhibitor Identifications Reveal Targeting Opportunity for the Atypical MAPK Kinase ERK3". International Journal of Molecular Sciences 21, nr 21 (26.10.2020): 7953. http://dx.doi.org/10.3390/ijms21217953.
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Extracellular signal-regulated kinase 3 (ERK3), known also as mitogen-activated protein kinase 6 (MAPK6), is an atypical member of MAPK kinase family, which has been poorly studied. Little is known regarding its function in biological processes, yet this atypical kinase has been suggested to play important roles in the migration and invasiveness of certain cancers. The lack of tools, such as a selective inhibitor, hampers the study of ERK3 biology. Here, we report the crystal structure of the kinase domain of this atypical MAPK kinase, providing molecular insights into its distinct ATP binding pocket compared to the classical MAPK ERK2, explaining differences in their inhibitor binding properties. Medium-scale small molecule screening identified a number of inhibitors, several of which unexpectedly exhibited remarkably high inhibitory potencies. The crystal structure of CLK1 in complex with CAF052, one of the most potent inhibitors identified for ERK3, revealed typical type-I binding mode of the inhibitor, which by structural comparison could likely be maintained in ERK3. Together with the presented structural insights, these diverse chemical scaffolds displaying both reversible and irreversible modes of action, will serve as a starting point for the development of selective inhibitors for ERK3, which will be beneficial for elucidating the important functions of this understudied kinase.
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Harris, Christopher M., Sage E. Foley, Eric R. Goedken, Mark Michalak, Sara Murdock i Noel S. Wilson. "Merits and Pitfalls in the Characterization of Covalent Inhibitors of Bruton’s Tyrosine Kinase". SLAS DISCOVERY: Advancing the Science of Drug Discovery 23, nr 10 (10.07.2018): 1040–50. http://dx.doi.org/10.1177/2472555218787445.
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In vitro analysis of covalent inhibitors requires special consideration, due to the time-dependent and typically irreversible nature of their target interaction. While many analyses are reported for the characterization of a final candidate, it is less clear which are most useful in the lead optimization phase of drug discovery. In the context of identifying covalent inhibitors of Bruton’s tyrosine kinase (BTK), we evaluated multiple techniques for characterizing covalent inhibitors. Several methods qualitatively support the covalent mechanism of action or support a particular aspect of interaction but were not otherwise informative to differentiate inhibitors. These include the time dependence of IC50, substrate competition, mass spectrometry, and recovery of function after inhibitor removal at the biochemical and cellular level. A change in IC50 upon mutation of the targeted BTK C481 nucleophile or upon removal of the electrophilic moiety of the inhibitor was not always a reliable indicator of covalent inhibition. Determination of kinact and KI provides a quantitative description of covalent interactions but was challenging at scale and frequently failed to provide more than the ratio of the two values, kinact/KI. Overall, a combination of approaches is required to assess time-dependent, covalent, and irreversible inhibitors in a manner suitable to reliably advance drug candidates.
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Kuhn, Deborah J., Qing Chen, Peter M. Voorhees, John S. Strader, Kevin D. Shenk, Congcong M. Sun, Susan D. Demo, Mark K. Bennett, Fred W. van Leeuwen i Robert Z. Orlowski. "The Novel, Irreversible Proteasome Inhibitor PR-171 Demonstrates Potent Anti-Tumor Activity in Pre-Clinical Models of Multiple Myeloma, and Overcomes Bortezomib Resistance." Blood 108, nr 11 (16.11.2006): 3461. http://dx.doi.org/10.1182/blood.v108.11.3461.3461.
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Abstract Introduction: The ubiquitin-proteasome pathway has been validated as a therapeutic target with the approval of the small molecule proteasome inhibitor, bortezomib (VELCADE®), in multiple myeloma and non-Hodgkin lymphoma. However, the overall response rate of patients with multiple myeloma in phase III clinical trials was 43%, underscoring the need for a next generation of inhibitors with the potential for greater efficacy. Methods: PR-171 is a novel, tetrapeptide epoxomicin-related inhibitor that binds the proteasome irreversibly, and our objectives were to evaluate its activity and mechanism of action in pre-clinical models of multiple myeloma. Results: PR-171 potently bound and inhibited the chymotrypsin-like subunit of the proteasome in vitro, in cellulo, and in vivo at low concentrations. At higher concentrations, however, unlike bortezomib, which targeted the chymotrypsin-like and peptidyl-glutamyl peptide hydrolyzing activities in vivo, PR-171 also displayed significant inhibition of the trypsin-like and the peptidyl-glutamyl peptide hydrolyzing activities. PR-171-induced proteasome inhibition was associated with accumulation of polyubiquitinated substrates and pro-apoptotic Bax. Brief pulse PR-171 exposure, which simulates the in vivo pharmacokinetics of bortezomib, led to PR-171-mediated inhibition of cellular proliferation linked to induction of caspase-3-dependent apoptosis through both intrinsic (caspase-9) and extrinsic (caspase-8-dependent) pathways. Pretreatment with caspase-3, -8, and -9 inhibitors rescued the anti-proliferative effect of PR-171. Furthermore, pulse PR-171 treatment activated c-Jun-N-terminal kinase, a key-signaling molecule in proteasome inhibitor-induced apoptosis, and cleavage of poly-ADP-ribose polymerase, while abrogation of c-Jun-N-terminal kinase signaling with a dominant-negative c-Jun inhibited PR-171-induced effects. PR-171 displayed enhanced anti-proliferative activity compared to bortezomib in multiple myeloma cell lines and freshly isolated patient-derived CD138+ plasma cells, associated with enhanced phosphorylation of c-Jun-N-terminal kinase and capase-3, -8, and -9 activation. Lastly, PR-171 was a potent inhibitor of proliferation in a multiple myeloma cell line model resistant to bortezomib and in isolates from two patients, one with primary and the other with acquired bortezomib-resistance. Conclusions: These data indicate that PR-171 has enhanced activity against preclinical models of multiple myeloma, perhaps owing to its irreversible binding and subunit specificity, and provide a rationale for its translation into the clinic.
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Chung, Vincent, Ling Wang, Margaret S. Fletcher, Erminia Massarelli, Karen L. Reckamp, Mihaela C. Cristea, Nikeeta Prajapati i in. "First-time in-human study of VMD-928, an allosteric and irreversible TrkA selective inhibitor, in patients with solid tumors or lymphoma." Journal of Clinical Oncology 37, nr 15_suppl (20.05.2019): TPS3146. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.tps3146.
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TPS3146 Background: Tropomysin receptor kinase A (TrkA) is a protein encoded by the NTRK1 gene. NTRK fusions involving the kinase domain are oncogenic for multiple tumor types and larotrectinib was recently approved for advanced solid tumors harboring NTRK gene fusions. Larotrectinib, an ATP-competitive, reversible pan-TrkA/B/C inhibitor, has shown impressive response rates in patients harboring these fusions; however, resistance can develop due to acquired ATP-site mutations. This has been previously identified in other oncogenic driver kinases such as ALK and EGFR treated with ATP-competitive kinase inhibitors. A newly approved allosteric ALK/EGFR inhibitor brigatinib was able to clinically overcome acquired resistance of many ATP-competitive ALK/EGFR inhibitors (1). Also, irreversible EGFR inhibitors such as afatinib (ATP-competitive) were active against tumors resistant to first-generation inhibitors (2), although their efficacy can be compromised by acquired ATP-site mutations (3). VMD-928 is the first oral small-molecule TrkA (NTRK1) selective inhibitor with dual allosteric and irreversible mechanisms of action. It inhibits TrkA non-competitively at an allosteric (non-ATP) site and has no resistance in vitro to acquired ATP-site mutations such as G667C. VMD-928 in vitro has little or no activity against 348 other kinases including TrkB (NTRK2) and TrkC (NTRK3). We are conducting the first time in human phase 1 trial of oral VMD-928, a novel allosteric and irreversible TrkA selective inhibitor. Methods: This is an open label, Phase 1 study investigating the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of oral VMD-928 in adults with advanced solid tumors or lymphoma (NCT03556228). In part 1 of the study, an accelerated titration scheme will be utilized to determine the recommended phase 2 dose and evaluate PK / PD of VMD-928. In part 2, expansion cohorts including patients with thymic, pancreatic, triple-negative breast carcinoma, or solid tumors with TrkA alterations will be accrued to further evaluate safety and efficacy. Part 3 of the study will characterize the biologically active dose. The study is open and accruing patients at City of Hope. Clinical trial information: NCT03556228.
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Liclican, Albert, Weimei Xing, Loredana Serafini, Ting Wang, Kathy Brendza, Justin Lutz, Adrian S. Ray, Brian Schultz, Roman Sakowicz i Joy Y. Feng. "Biochemical Characterization of GS-4059 As a Potent and Selective Covalent Irreversible Inhibitor of Bruton's Tyrosine Kinase". Blood 128, nr 22 (2.12.2016): 1594. http://dx.doi.org/10.1182/blood.v128.22.1594.1594.
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Abstract Introduction:Bruton's tyrosine kinase (BTK) plays a crucial role in B-cell development, differentiation, and signaling in the B-cell receptor (BCR) signaling pathway, and is a validated target for aberrant B-cell activity in malignancy and autoimmune diseases. GS-4059 (ONO-4059) is a selective, once-daily, oral inhibitor of BTK with clinical activity against a number of relapsed/refractory B-cell malignancies. GS-4059 was designed to specifically form a covalent bond with a cysteine residue in the BTK active site. The studies presented here confirmed the biochemical mechanism of action of GS-4059, assessed the inactivation kinetics of BTK by GS-4059 and comparator compounds, and measured the selectivity of GS-4059 for BTK over other related kinases. These studies will help to establish pharmacokinetic-pharmacodynamic models to guide clinical studies, and the evaluation of potential for inhibition of other kinases will assist in understanding the safety of the molecule. Methods: The binding of GS-4059 to BTK was characterized using mass spectrometry to detect covalent adduct formation. Ibrutinib, a known irreversible covalent inhibitor, and staurosporine, a known reversible noncovalent inhibitor, were used as positive controls. The covalent nature of GS-4059 was further tested by chasing with excess amount of ibrutinib. GS-4059 and other covalent, irreversible inhibitors of BTK including CC-292, acalabrutinib, and ibrutinib were studied to determine the inactivation kinetics of BTK and related kinases, such as epidermal growth factor receptor (EGFR) and IL2-inducible T-cell kinase (ITK), for these compounds. The rate of enzyme inactivation was studied as a function of inhibitor concentration using a Sox-based fluorescence assay that allows real-time measurement of enzyme activity. Results: Mass spectrometry studies showed that GS-4059 is a covalent inhibitor of BTK, based on an observed mass shift of BTK following preincubation with GS-4059 (Figure 1). This mass shift was consistent with the molecular weight of GS-4059. The irreversibility of GS-4059 binding was further demonstrated by the observation that GS-4059 could not be displaced from BTK by chasing with ibrutinib, as measured by mass spectrometry. GS-4059 efficiently inactivated BTK with a rate constant kinact/Ki of 2.4 ± 0.6 ´ 104 M-1s-1, similar to that of the covalent BTK inhibitors CC-292 and acalabrutinib, but >10 times lower than that of ibrutinib (Figure 2, Figure 3, and Table 1). In addition, GS-4059 is a poor inhibitor of the related kinases EGFR and ITK, supporting the clinical observation of a favorable safety profile for GS-4059 (Table 1). Conclusions: In summary, GS-4059 is a potent and selective covalent irreversible inhibitor of BTK with a different selectivity profile than other BTK inhibitors, and warrants further studies against B-cell malignancies and autoimmune diseases. Figure 1 Mass Spectrometry Analysis Showing Mass Shift of BTK upon Binding of GS-4059. The reversible noncovalent inhibitor staurosporine and the irreversible covalent inhibitor ibrutinib were used as controls. Figure 1. Mass Spectrometry Analysis Showing Mass Shift of BTK upon Binding of GS-4059. The reversible noncovalent inhibitor staurosporine and the irreversible covalent inhibitor ibrutinib were used as controls. Figure 2 BTK Product Formation Progress Curves in the Presence of Increasing Concentrations of GS-4059, CC-292, Acalabrutinib, and Ibrutinib. Legends to the right of curves indicate compound concentrations. Figure 2. BTK Product Formation Progress Curves in the Presence of Increasing Concentrations of GS-4059, CC-292, Acalabrutinib, and Ibrutinib. Legends to the right of curves indicate compound concentrations. Figure 3 Plots of kobs as a Function of Inhibitor Concentration for GS-4059, CC-292, Acalabrutinib, and Ibrutinib. Figure 3. Plots of kobs as a Function of Inhibitor Concentration for GS-4059, CC-292, Acalabrutinib, and Ibrutinib. Disclosures Liclican: Gilead Sciences: Employment, Equity Ownership. Xing:Gilead Sciences: Employment, Equity Ownership. Serafini:Gilead Sciences: Employment, Equity Ownership. Wang:Gilead Sciences: Employment, Equity Ownership. Brendza:Gilead Sciences: Employment, Equity Ownership. Lutz:Gilead Sciences: Employment, Equity Ownership. Ray:Gilead Sciences: Employment, Equity Ownership. Schultz:Gilead Sciences: Employment, Equity Ownership. Sakowicz:Gilead Sciences: Employment, Equity Ownership. Feng:Gilead Sciences: Employment, Equity Ownership.