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Journal articles on the topic 'ATP-competitive'

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Author: Grafiati

Published: 1 April 2023

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1

Lebakken, Connie S., Laurie J. Reichling, Jason M. Ellefson, and Steven M. Riddle. "Detection of Allosteric Kinase Inhibitors by Displacement of Active Site Probes." Journal of Biomolecular Screening 17, no. 6 (March 26, 2012): 813–21. http://dx.doi.org/10.1177/1087057112439889.

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Non–adenosine triphosphate (ATP) competitive, allosteric inhibitors provide a promising avenue to develop highly selective small-molecule kinase inhibitors. Although this class of compounds is growing, detection of such inhibitors can be challenging as standard kinase activity assays preferentially detect compounds that bind to active kinases in an ATP competitive manner. We have previously described a time-resolved fluorescence resonance energy transfer (TR-FRET)–based kinase binding assay using the competitive displacement of ATP competitive active site fluorescent probes (“tracers”). Although this format has gained acceptance, published data with this and related formats are almost entirely without examples of non-ATP competitive compounds. Thus, this study addresses whether this format is useful for non-ATP competitive inhibitors. To this end, 15 commercially available non-ATP competitive inhibitors were tested for their ability to displace ATP competitive probes. Despite the diversity of both compound structures and their respective targets, 14 of the 15 compounds displaced the tracers with IC50 values comparable to literature values. We conclude that such binding assays are well suited for the study of non-ATP competitive inhibitors. In addition, we demonstrate that allosteric inhibitors of BCR-Abl and MEK bind preferentially to the nonphosphorylated (i.e., inactive) form of the kinase, indicating that binding assays may be a preferred format in some cases.

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2

Agius, Michael P., Kristin Ko, Taylor K. Johnson, Sameer Phadke, and Matthew B. Soellner. "Conformation-tunable ATP-competitive kinase inhibitors." Chemical Communications 58, no. 21 (2022): 3541–44. http://dx.doi.org/10.1039/d1cc06893h.

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3

Garuti, L., M. Roberti, and G. Bottegoni. "Non-ATP Competitive Protein Kinase Inhibitors." Current Medicinal Chemistry 17, no. 25 (September 1, 2010): 2804–21. http://dx.doi.org/10.2174/092986710791859333.

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4

Lee, Byung-Il, Hyung-Jun Ahn, Ki-Cheol Han, Dae-Ro Ahn, and Dong-Yun Shin. "Pyrogallin, an ATP-Competitive Inhibitor of JAK3." Bulletin of the Korean Chemical Society 32, no. 3 (March 20, 2011): 1077–79. http://dx.doi.org/10.5012/bkcs.2011.32.3.1077.

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5

Schenone, S., C. Brullo, F. Musumeci, M. Radi, and M. Botta. "ATP-Competitive Inhibitors of mTOR: An Update." Current Medicinal Chemistry 18, no. 20 (July 1, 2011): 2995–3014. http://dx.doi.org/10.2174/092986711796391651.

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6

Lazaro, Glorianne, Eleftherios Kostaras, and Igor Vivanco. "Inhibitors in AKTion: ATP-competitive vs allosteric." Biochemical Society Transactions 48, no. 3 (May 26, 2020): 933–43. http://dx.doi.org/10.1042/bst20190777.

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Aberrant activation of the PI3K pathway is one of the commonest oncogenic events in human cancer. AKT is a key mediator of PI3K oncogenic function, and thus has been intensely pursued as a therapeutic target. Multiple AKT inhibitors, broadly classified as either ATP-competitive or allosteric, are currently in various stages of clinical development. Herein, we review the evidence for AKT dependence in human tumours and focus on its therapeutic targeting by the two drug classes. We highlight the future prospects for the development and implementation of more effective context-specific AKT inhibitors aided by our increasing knowledge of both its regulation and some previously unrecognised non-canonical functions.

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7

Parrish, Cynthia A., Nicholas D. Adams, Kurt R. Auger, Joelle L. Burgess, Jeffrey D. Carson, Amita M. Chaudhari, Robert A. Copeland, et al. "Novel ATP-Competitive Kinesin Spindle Protein Inhibitors." Journal of Medicinal Chemistry 50, no. 20 (October 2007): 4939–52. http://dx.doi.org/10.1021/jm070435y.

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8

Ito, Masahiro, Misa Iwatani, Yusuke Kamada, Satoshi Sogabe, Shoichi Nakao, Toshio Tanaka, Tomohiro Kawamoto, Samuel Aparicio, Atsushi Nakanishi, and Yasuhiro Imaeda. "Discovery of selective ATP-competitive eIF4A3 inhibitors." Bioorganic & Medicinal Chemistry 25, no. 7 (April 2017): 2200–2209. http://dx.doi.org/10.1016/j.bmc.2017.02.035.

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9

Zarębska, Ewa A., Krzysztof Kusy, Ewa M. Słomińska, Łukasz Kruszyna, and Jacek Zieliński. "Plasma Nucleotide Dynamics during Exercise and Recovery in Highly Trained Athletes and Recreationally Active Individuals." BioMed Research International 2018 (October 9, 2018): 1–11. http://dx.doi.org/10.1155/2018/4081802.

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Circulating plasma ATP is able to regulate local skeletal muscle blood flow and 02 delivery causing considerable vasodilatation during exercise. We hypothesized that sport specialization and specific long-term training stimuli have an impact on venous plasma [ATP] and other nucleotides concentration. Four athletic groups consisting of sprinters (n=11; age range 21–30 yr), endurance-trained athletes (n=16; age range 18–31 yr), futsal players (n=14; age range 18–30 yr), and recreationally active individuals (n=12; age range 22–33 yr) were studied. Venous blood samples were collected at rest, during an incremental treadmill test, and during recovery. Baseline [ATP] was 759±80 nmol·l−1 in competitive athletes and 680±73 nmol·l−1 in controls and increased during exercise by ~61% in competitive athletes and by ~31% in recreationally active participants. We demonstrated a rapid increase in plasma [ATP] at exercise intensities of 83–87% of VO2max in competitive athletes and 94% in controls. Concentrations reported after 30 minutes of recovery were distinct from those obtained preexercise in competitive athletes (P<0.001) but not in controls (P=0.61). We found a correlation between total-body skeletal muscle mass and resting and maximal plasma [ATP] in competitive athletes (r=0.81 and r=0.75, respectively). In conclusion, sport specialization is significantly related to plasma [ATP] at rest, during exercise, and during maximal effort. Intensified exercise-induced plasma [ATP] increases may contribute to more effective vessel dilatation during exercise in highly trained athletes than in recreational runners. The most rapid increase in ATP concentration was associated with the respiratory compensation point. No differences between groups of competitive athletes were observed during the recovery period suggesting a similar pattern of response after exercise. Total-body skeletal muscle mass is indirectly related to plasma [ATP] in highly trained athletes.

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10

Lyle, S., D. H. Geller, K. Ng, J. Stanczak, J. Westley, and N. B. Schwartz. "Kinetic mechanism of adenosine 5′-phosphosulphate kinase from rat chondrosarcoma." Biochemical Journal 301, no. 2 (July 15, 1994): 355–59. http://dx.doi.org/10.1042/bj3010355.

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Biosynthesis of the activated sulphate donor adenosine 3′-phosphate 5′-phosphosulphate (PAPS) involves the sequential action of two enzyme activities. ATP-sulphurylase catalyses the formation of APS (adenosine 5′-phosphosulphate) from ATP and free sulphate, and APS is then phosphorylated by APS kinase to produce PAPS. Initial-velocity patterns for rat chondrosarcoma APS kinase indicate a single-displacement formal mechanism with KmAPS 76 nM and KmATP = 24 microM. Inhibition studies using analogues of substrates and products were carried out to determine the reaction mechanism. An analogue of PAPS, adenosine 3′-phosphate 5′-[beta-methylene]phosphosulphate, exhibited competitive inhibition with APS and non-competitive inhibition with ATP. An analogue of APS, adenosine 5′-[beta-methylene]phosphosulphate was also competitive with APS and non-competitive with ATP. Adenosine 5′-[beta gamma-imido]triphosphate showed competitive inhibition with respect to ATP and produced mixed-type inhibition, with a pronounced intercept effect and a small slope effect, with respect to APS. These results are in accord with the formulation of the predominant pathway as a steady-state ordered mechanism with APS as the leading substrate and PAPS as the final product released.

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11

Takahashi, Hideyuki, and Hideo Namiki. "Mechanism of membrane redistribution of protein kinase C by its ATP-competitive inhibitors." Biochemical Journal 405, no. 2 (June 27, 2007): 331–40. http://dx.doi.org/10.1042/bj20070299.

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ATP-competitive inhibitors of PKC (protein kinase C) such as the bisindolylmaleimide GF 109203X, which interact with the ATP-binding site in the PKC molecule, have also been shown to affect several redistribution events of PKC. However, the reason why these inhibitors affect the redistribution is still controversial. In the present study, using immunoblot analysis and GFP (green fluorescent protein)-tagged PKC, we showed that, at commonly used concentrations, these ATP-competitive inhibitors alone induced redistribution of DAG (diacylglycerol)-sensitive PKCα, PKCβII, PKCδ and PKCϵ, but not atypical PKCζ, to the endomembrane or the plasma membrane. Studies with deletion and point mutants showed that the DAG-sensitive C1 domain of PKC was required for membrane redistribution by these inhibitors. Furthermore, membrane redistribution was prevented by the aminosteroid PLC (phospholipase C) inhibitor U-73122, although an ATP-competitive inhibitor had no significant effect on acute DAG generation. Immunoblot analysis showed that an ATP-competitive inhibitor enhanced cell-permeable DAG analogue- or phorbol-ester-induced translocation of endogenous PKC. Furthermore, these inhibitors also enhanced [3H]phorbol 12,13-dibutyrate binding to the cytosolic fractions from PKCα–GFP-overexpressing cells. These results clearly demonstrate that ATP-competitive inhibitors cause redistribution of DAG-sensitive PKCs to membranes containing endogenous DAG by altering the DAG sensitivity of PKC and support the idea that the inhibitors destabilize the closed conformation of PKC and make the C1 domain accessible to DAG. Most importantly, our findings provide novel insights for the interpretation of studies using ATP-competitive inhibitors, and, especially, suggest caution about the interpretation of the relationship between the redistribution and kinase activity of PKC.

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12

Quartieri, Francesca, Marcella Nesi, Nilla R. Avanzi, Daniela Borghi, Elena Casale, Emiliana Corti, Ulisse Cucchi, et al. "Identification of unprecedented ATP-competitive choline kinase inhibitors." Bioorganic & Medicinal Chemistry Letters 51 (November 2021): 128310. http://dx.doi.org/10.1016/j.bmcl.2021.128310.

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13

Tang, Colin P., Owen Clark, John R. Ferrarone, Carl Campos, Alshad S. Lalani, John D. Chodera, Andrew M. Intlekofer, Olivier Elemento, and Ingo K. Mellinghoff. "GCN2 kinase activation by ATP-competitive kinase inhibitors." Nature Chemical Biology 18, no. 2 (December 23, 2021): 207–15. http://dx.doi.org/10.1038/s41589-021-00947-8.

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14

Freeman-Cook, Kevin D., Christopher Autry, Gary Borzillo, Deborah Gordon, Elsa Barbacci-Tobin, Vincent Bernardo, David Briere, et al. "Design of Selective, ATP-Competitive Inhibitors of Akt." Journal of Medicinal Chemistry 53, no. 12 (June 24, 2010): 4615–22. http://dx.doi.org/10.1021/jm1003842.

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15

Tunnicliff, G., and T. L. Youngs. "Competitive Inhibition of Mouse Brain -Aminobutyrate Aminotransferase by ATP." Experimental Biology and Medicine 192, no. 1 (October 1, 1989): 11–15. http://dx.doi.org/10.3181/00379727-192-42947.

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16

Papa, F. R. "Bypassing a Kinase Activity with an ATP-Competitive Drug." Science 302, no. 5650 (November 28, 2003): 1533–37. http://dx.doi.org/10.1126/science.1090031.

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17

Huck, Bayard R., and Igor Mochalkin. "Recent progress towards clinically relevant ATP-competitive Akt inhibitors." Bioorganic & Medicinal Chemistry Letters 27, no. 13 (July 2017): 2838–48. http://dx.doi.org/10.1016/j.bmcl.2017.04.090.

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18

Quintás-Cardama, A. "Experimental non-ATP-competitive therapies for chronic myelogenous leukemia." Leukemia 22, no. 5 (March 6, 2008): 932–40. http://dx.doi.org/10.1038/leu.2008.47.

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19

Barf, Tjeerd, Allard Kaptein, Sander de Wilde, Ruud van der Heijden, Richard van Someren, Dennis Demont, Carsten Schultz-Fademrecht, et al. "Structure-based lead identification of ATP-competitive MK2 inhibitors." Bioorganic & Medicinal Chemistry Letters 21, no. 12 (June 2011): 3818–22. http://dx.doi.org/10.1016/j.bmcl.2011.04.018.

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20

Zhang, Dingwa, Deyong He, Xiaoliang Pan, and Lijun Liu. "Systematic profiling of ATP response to acquired drug-resistant EGFR family kinase mutations." Journal of the Serbian Chemical Society 85, no. 10 (2020): 1265–78. http://dx.doi.org/10.2298/jsc191124028z.

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Kinase-targeted cancer therapy (KTCT) with ATP-competitive inhibitors has been widely applied in clinics. However, a number of kinase missense mutations were observed to confer acquired drug resistance during therapy, largely limiting the clinical application of kinase inhibitors in KTCT. Instead of directly influencing inhibitor binding, kinase mutations can also cause generic resistance to ATP-competitive inhibitors by increasing ATP affinity. Herein, the intermolecular interaction of the ATP molecule with clinically observed drug-resistant EGFR family kinase mutations involved in human cancer are systematically characterize. Rigorous quantum mechanics/molecular mechanics (QM/MM) calculation and empirical Poisson?Boltzmann/surface area (PB/SA) analysis as well as in vitro kinase assay and surface plasmon resonance analysis were integrated to explore the binding capability of ATP to mutant residues in the structural context of the kinase domain, which resulted in a comprehensive profile of ATP response to acquired drug-resistant mutations of four EGFR family kinases (EGFR/ErbB1, ErbB2, ErbB3 and ErbB4). From the profile, it was possible to identify those potent mutations that may influence ATP binding significantly; such mutations are potential candidates to cause generic resistance for ATP-competitive inhibitors. Consequently, the well documented generic drug-resistant mutation EGFR T790M and its counterpart ErbB2 T798M are found to increase ATP affinity by establishing an additional S?? interaction between the side-chain thioether group of the mutant Met residue and the aromatic adenine moiety of the ATP molecule, while EGFR D761Y is identified as a new generic drug-resistant mutation that can increase ATP affinity by eliminating unfavorable electrostatic repulsion. In contrast, ErbB2 K753E and T768I are considered to be two generic drug-sensitive mutations that can decrease ATP affinity by unfavorable charge reversal and by impairing favorable polar interaction, respectively. In addition, the EGFR L858R mutation is located at the kinase activation loop and nearby the kinase active site, thus largely complicating the multiply dependent relationship of kinase, ATP and inhibitor, which therefore exhibits divergent effects on different tested inhibitors.

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21

Pinzi, Luca. "On the development of B-Raf inhibitors acting through innovative mechanisms." F1000Research 11 (April 26, 2022): 237. http://dx.doi.org/10.12688/f1000research.108761.2.

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B-Raf is a protein kinase participating to the regulation of many biological processes in cells. Several studies have demonstrated that this protein is frequently upregulated in human cancers, especially when it bears activating mutations. In the last years, few ATP-competitive inhibitors of B-Raf have been marketed for the treatment of melanoma and are currently under clinical evaluation on a variety of other types of cancer. Although the introduction of drugs targeting B-Raf has provided significant advances in cancer treatment, responses to ATP-competitive inhibitors remain limited, mainly due to selectivity issues, side effects, narrow therapeutic windows, and the insurgence of drug resistance. Impressive research efforts have been made so far towards the identification of novel ATP-competitive modulators with improved efficacy against cancers driven by mutant Raf monomers and dimers, some of them showing good promises. However, several limitations could still be envisioned for these compounds, according to literature data. Besides, increased attentions have arisen around approaches based on the design of allosteric modulators, polypharmacology, proteolysis targeting chimeras (PROTACs) and drug repurposing for the targeting of B-Raf proteins. The design of compounds acting through such innovative mechanisms is rather challenging. However, valuable therapeutic opportunities can be envisioned on these drugs, as they act through innovative mechanisms in which limitations typically observed for approved ATP-competitive B-Raf inhibitors are less prone to emerge. In this article, current approaches adopted for the design of non-ATP competitive inhibitors targeting B-Raf are described, discussing also on the possibilities, ligands acting through such innovative mechanisms could provide for the obtainment of more effective therapies.

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22

Pinzi, Luca. "On the development of B-Raf inhibitors acting through innovative mechanisms." F1000Research 11 (April 26, 2022): 237. http://dx.doi.org/10.12688/f1000research.108761.2.

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B-Raf is a protein kinase participating to the regulation of many biological processes in cells. Several studies have demonstrated that this protein is frequently upregulated in human cancers, especially when it bears activating mutations. In the last years, few ATP-competitive inhibitors of B-Raf have been marketed for the treatment of melanoma and are currently under clinical evaluation on a variety of other types of cancer. Although the introduction of drugs targeting B-Raf has provided significant advances in cancer treatment, responses to ATP-competitive inhibitors remain limited, mainly due to selectivity issues, side effects, narrow therapeutic windows, and the insurgence of drug resistance. Impressive research efforts have been made so far towards the identification of novel ATP-competitive modulators with improved efficacy against cancers driven by mutant Raf monomers and dimers, some of them showing good promises. However, several limitations could still be envisioned for these compounds, according to literature data. Besides, increased attentions have arisen around approaches based on the design of allosteric modulators, polypharmacology, proteolysis targeting chimeras (PROTACs) and drug repurposing for the targeting of B-Raf proteins. The design of compounds acting through such innovative mechanisms is rather challenging. However, valuable therapeutic opportunities can be envisioned on these drugs, as they act through innovative mechanisms in which limitations typically observed for approved ATP-competitive B-Raf inhibitors are less prone to emerge. In this article, current approaches adopted for the design of non-ATP competitive inhibitors targeting B-Raf are described, discussing also on the possibilities, ligands acting through such innovative mechanisms could provide for the obtainment of more effective therapies.

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23

Pinzi, Luca. "On the development of B-Raf inhibitors acting through innovative mechanisms." F1000Research 11 (February 25, 2022): 237. http://dx.doi.org/10.12688/f1000research.108761.1.

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B-Raf is a protein kinase participating to the regulation of many biological processes in cells. Recent studies have demonstrated that this protein is frequently overactivated in human cancers, especially when it bears activating mutations. In recent years, few ATP-competitive inhibitors of B-Raf have been marketed for the treatment of melanoma and are currently under clinical evaluation on a variety of other types of cancer. Although the introduction of drugs targeting B-Raf has provided significant advances in cancer treatment, responses to such ATP-competitive inhibitors remain limited, mainly due to selectivity issues, side effects, narrow therapeutic windows, and the insurgence of drug resistance. Impressive research efforts have been made so far towards the identification of novel ATP-competitive modulators with improved efficacy against cancers driven by mutant Raf monomers and dimers, some of them showing good premises. However, several limitations could still be envisioned for these compounds, according to recent literature data. Besides, increased attentions have recently arisen around approaches based on the design of allosteric modulators, polypharmacology, PROTACs and drug repurposing for the targeting of B-Raf proteins. The design of compounds acting through such innovative mechanisms is rather challenging. However, novel valuable therapeutic opportunities can be envisioned on these drugs, as they act through innovative mechanisms in which limitations typically observed for approved ATP-competitive B-Raf inhibitors are less prone to emerge. In this article, the most recent approaches adopted for the design of non-ATP competitive inhibitors targeting B-Raf are described, discussing also on the possibilities, ligands acting through such innovative mechanisms could provide for the obtainment of more effective therapies.

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24

Wilson, Brice A. P., Muhammad S. Alam, Tad Guszczynski, Michal Jakob, Shilpa R. Shenoy, Carter A. Mitchell, Ekaterina I. Goncharova, et al. "Discovery and Characterization of a Biologically Active Non–ATP-Competitive p38 MAP Kinase Inhibitor." Journal of Biomolecular Screening 21, no. 3 (November 4, 2015): 277–89. http://dx.doi.org/10.1177/1087057115615518.

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Mitogen-activated protein kinase (MAPK) p38 is part of a broad and ubiquitously expressed family of MAPKs whose activity is responsible for mediating an intracellular response to extracellular stimuli through a phosphorylation cascade. p38 is central to this signaling node and is activated by upstream kinases while being responsible for activating downstream kinases and transcription factors via phosphorylation. Dysregulated p38 activity is associated with numerous autoimmune disorders and has been implicated in the progression of several types of cancer. A number of p38 inhibitors have been tested in clinical trials, with none receiving regulatory approval. One characteristic shared by all of the compounds that failed clinical trials is that they are all adenosine triphosphate (ATP)–competitive p38 inhibitors. Seeing this lack of mechanistic diversity as an opportunity, we screened ~32,000 substances in search of novel p38 inhibitors. Among the inhibitors discovered is a compound that is both non–ATP competitive and biologically active in cell-based models for p38 activity. This is the first reported discovery of a non–ATP-competitive p38 inhibitor that is active in cells and, as such, may enable new pharmacophore designs for both therapeutic and basic research to better understand and exploit non–ATP-competitive inhibitors of p38 activity.

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25

Khandekar, Sanjay S., Bingbing Feng, Tracey Yi, Susan Chen, Nicholas Laping, and Neal Bramson. "A Liquid Chromatography/Mass Spectrometry-Based Method for the Selection of ATP Competitive Kinase Inhibitors." Journal of Biomolecular Screening 10, no. 5 (August 2005): 447–55. http://dx.doi.org/10.1177/1087057105274846.

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The currently approved kinase inhibitors for therapeutic uses and a number of kinase inhibitors that are undergoing clinical trials are directed toward the adenosine triphosphate (ATP) binding site of protein kinases. The 5β-fluorosulfonylbenzoyl 5'-adenosine (FSBA) is an ATP-affinity reagent that covalently modifies a conserved lysine present in the nucleotide-binding site of most kinases. The authors have developed a liquid chromatography/mass spectrometry-basedmethod tomonitor binding ofATP competitive protein kinase inhibitors using FSBAas a nonselective activity-based probe for protein kinases. Their method provides a general, rapid, and reproducible means to screen and validate selective ATP competitive inhibitors of protein kinases.

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26

Chung, Vincent, Ling Wang, Margaret S. Fletcher, Erminia Massarelli, Karen L. Reckamp, Mihaela C. Cristea, Nikeeta Prajapati, et al. "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, no. 15_suppl (May 20, 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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27

Schenone, S., C. Brullo, and M. Botta. "Small Molecules ATP-Competitive Inhibitors of FLT3: A Chemical Overview." Current Medicinal Chemistry 15, no. 29 (December 1, 2008): 3113–32. http://dx.doi.org/10.2174/092986708786848613.

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28

Ma, Bin, Doug Marcotte, Murugan Paramasivam, Klaus Michelsen, Ti Wang, Andrea Bertolotti-Ciarlet, John Howard Jones, et al. "ATP-Competitive MLKL Binders Have No Functional Impact on Necroptosis." PLOS ONE 11, no. 11 (November 10, 2016): e0165983. http://dx.doi.org/10.1371/journal.pone.0165983.

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29

Karni, Rotem, Sarit Mizrachi, Ella Reiss-Sklan, Aviv Gazit, Oded Livnah, and Alexander Levitzki. "The pp60c-Src inhibitor PP1 is non-competitive against ATP." FEBS Letters 537, no. 1-3 (January 29, 2003): 47–52. http://dx.doi.org/10.1016/s0014-5793(03)00069-3.

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30

Shen, Guobing, Miaoqing Liu, Jianjun Lu, and Tao Meng. "Practical synthesis of Vistusertib (AZD2014), an ATP competitive mTOR inhibitor." Tetrahedron Letters 60, no. 52 (December 2019): 151333. http://dx.doi.org/10.1016/j.tetlet.2019.151333.

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31

Wu, Ke, Jingzhi Pang, Dong Song, Ying Zhu, Congwen Wu, Tianqu Shao, and Haifeng Chen. "Selectivity Mechanism of ATP-Competitive Inhibitors for PKB and PKA." Chemical Biology & Drug Design 86, no. 1 (November 28, 2014): 9–18. http://dx.doi.org/10.1111/cbdd.12472.

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32

Freeman-Cook, Kevin D., Christopher Autry, Gary Borzillo, Deborah Gordon, Elsa Barbacci-Tobin, Vincent Bernardo, David Briere, et al. "Corrections to Design of Selective, ATP-Competitive Inhibitors of Akt." Journal of Medicinal Chemistry 53, no. 15 (August 12, 2010): 5895. http://dx.doi.org/10.1021/jm100769x.

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33

Garc�a-Echeverr�a, Carlos, Peter Traxler, and Dean B. Evans. "ATP site-directed competitive and irreversible inhibitors of protein kinases." Medicinal Research Reviews 20, no. 1 (January 2000): 28–57. http://dx.doi.org/10.1002/(sici)1098-1128(200001)20:1<28::aid-med2>3.0.co;2-2.

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34

Wang, Ruixiu, and James E. Thompson. "Detection of ATP Competitive Protein Kinase Inhibition by Western Blotting." Analytical Biochemistry 299, no. 1 (December 2001): 110–12. http://dx.doi.org/10.1006/abio.2001.5410.

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35

Kirkland, Lindsay O., and Campbell McInnes. "Non-ATP competitive protein kinase inhibitors as anti-tumor therapeutics." Biochemical Pharmacology 77, no. 10 (May 2009): 1561–71. http://dx.doi.org/10.1016/j.bcp.2008.12.022.

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36

Rosborough, Brian, Dàlia Raïch-Regué, Benjamin Matta, Keunwook Lee, Mark Boothby, Heth Turnquist, and Angus Thomson. "Rapamycin-resistant mTORC1 restrains dendritic cell B7-H1 expression that requires IL-1β to enhance regulatory T cell induction (P1349)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 63.27. http://dx.doi.org/10.4049/jimmunol.190.supp.63.27.

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Abstract Introduction: The mammalian Target of Rapamycin (mTOR) is a central regulator of dendritic cell (DC) function that performs the catalytic activity of mTOR complex (mTORC)1 and 2. mTORC2 functions independently from mTORC1 and is resistant to inhibition by rapamycin (RAPA); however, mTORC1 has both RAPA-sensitive and -resistant outputs. Our goal was to ascertain the role of RAPA-resistant mTOR in DC. Methods: WT C57BL/6 or B7-H1-/- bone marrow-derived DC were generated with the addition of RAPA or ATP-competitive mTOR inhibitor, which blocks all mTOR signaling. DC lacking rictor, an mTORC2-specific subunit, were generated from conditional rictor KO mice. DC induction of regulatory T cells (Treg) was determined in MLR, using BALB/c CD4+CD25- T cell responders. Results and Conclusion: RAPA and mTORC2 deletion reduced DC B7-H1 expression, but ATP-competitive mTOR inhibitors enhanced B7-H1 expression. Augmented B7-H1 expression was blocked by STAT3 inhibition and correlated with reduced expression of the STAT3 negative regulator, SOCS3. DC exposed to ATP-competitive mTOR inhibitors increased Treg induction, which was dependent on DC B7-H1. IL-1β neutralization additionally reduced Treg induction by B7-H1-/- ATP-competitive mTOR inhibitor-exposed DC, suggesting that IL-1β and B7-H1 act additively to promote Treg induction by these DC. These findings establish a RAPA-resistant mTORC1 pathway that acts through SOCS3 and STAT3 to regulate DC B7-H1 expression and Treg induction.

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Roulin, Didier, Nicolas Demartines, and Olivier Dormond. "ATP-competitive inhibitors of mTOR: new perspectives in the treatment of renal cell carcinoma." Biochemical Society Transactions 39, no. 2 (March 22, 2011): 492–94. http://dx.doi.org/10.1042/bst0390492.

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Targeting mTOR (mammalian target of rapamycin) is an effective approach in the treatment of advanced RCC (renal cell carcinoma). Rapamycin-like drugs (rapalogues) have shown clinical activities and have been approved for the treatment of RCC. Recently, with the development of ATP-competitive inhibitors of mTOR, therapies targeting mTOR have entered a new era. Here, we discuss the biological relevance of blocking mTOR in RCC and review the mechanisms of action of rapalogues in RCC. We also advance some perspectives on the use of ATP-competitive inhibitors of mTOR in RCC.

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Li, Chunqiong, Xuewen Zhang, Na Zhang, Yue Zhou, Guohui Sun, Lijiao Zhao, and Rugang Zhong. "Identification and Biological Evaluation of CK2 Allosteric Fragments through Structure-Based Virtual Screening." Molecules 25, no. 1 (January 6, 2020): 237. http://dx.doi.org/10.3390/molecules25010237.

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Casein kinase II (CK2) is considered as an attractive cancer therapeutic target, and recent efforts have been made to develop its ATP-competitive inhibitors. However, achieving selectivity with respect to related kinases remains challenging due to the highly conserved ATP-binding pocket of kinases. Allosteric inhibitors, by targeting the much more diversified allosteric site relative to the highly conserved ATP-binding pocket, might be a promising strategy with the enhanced selectivity and reduced toxicity than ATP-competitive inhibitors. The previous studies have highlighted the traditional serendipitousity of discovering allosteric inhibitors owing to the complicate allosteric modulation. In this current study, we identified the novel allosteric inhibitors of CK2α by combing structure-based virtual screening and biological evaluation methods. The structure-based pharmacophore model was built based on the crystal structure of CK2α-compound 15 complex. The ChemBridge fragment library was searched by evaluating the fit values of these molecules with the optimized pharmacophore model, as well as the binding affinity of the CK2α-ligand complexes predicted by Alloscore web server. Six hits forming the holistic interaction mechanism with the αD pocket were retained after pharmacophore- and Alloscore-based screening for biological test. Compound 3 was found to be the most potent non-ATP competitive CK2α inhibitor (IC50 = 13.0 μM) with the anti-proliferative activity on A549 cancer cells (IC50 = 23.1 μM). Our results provide new clues for further development of CK2 allosteric inhibitors as anti-cancer hits.

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O’Connor, Suzanne, Yann-Vaï Le Bihan, Isaac M. Westwood, Manjuan Liu, Oi Wei Mak, Gabriel Zazeri, Ana P. R. Povinelli, et al. "Discovery and Characterization of a Cryptic Secondary Binding Site in the Molecular Chaperone HSP70." Molecules 27, no. 3 (January 26, 2022): 817. http://dx.doi.org/10.3390/molecules27030817.

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Heat Shock Protein 70s (HSP70s) are key molecular chaperones that are overexpressed in many cancers and often associated with metastasis and poor prognosis. It has proven difficult to develop ATP-competitive, drug-like small molecule inhibitors of HSP70s due to the flexible and hydrophilic nature of the HSP70 ATP-binding site and its high affinity for endogenous nucleotides. The aim of this study was to explore the potential for the inhibition of HSP70 through alternative binding sites using fragment-based approaches. A surface plasmon resonance (SPR) fragment screen designed to detect secondary binding sites in HSP70 led to the identification by X-ray crystallography of a cryptic binding site in the nucleotide-binding domain (NBD) of HSP70 adjacent to the ATP-binding site. Fragment binding was confirmed and characterized as ATP-competitive using SPR and ligand-observed NMR methods. Molecular dynamics simulations were applied to understand the interactions with the protein upon ligand binding, and local secondary structure changes consistent with interconversion between the observed crystal structures with and without the cryptic pocket were detected. A virtual high-throughput screen (vHTS) against the cryptic pocket was conducted, and five compounds with diverse chemical scaffolds were confirmed to bind to HSP70 with micromolar affinity by SPR. These results identified and characterized a new targetable site on HSP70. While targeting HSP70 remains challenging, the new site may provide opportunities to develop allosteric ATP-competitive inhibitors with differentiated physicochemical properties from current series.

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Xu, Jimin, Jing Ai, Sheng Liu, Xia Peng, Linqian Yu, Meiyu Geng, and Fajun Nan. "Design and synthesis of 3,3′-biscoumarin-based c-Met inhibitors." Org. Biomol. Chem. 12, no. 22 (2014): 3721–34. http://dx.doi.org/10.1039/c4ob00364k.

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Napoleon, John V., Sarbjit Singh, Sandeep Rana, Mourad Bendjennat, Vikas Kumar, Smitha Kizhake, Nicholas Y. Palermo, Michel M. Ouellette, Tom Huxford, and Amarnath Natarajan. "Small molecule binding to inhibitor of nuclear factor kappa-B kinase subunit beta in an ATP non-competitive manner." Chemical Communications 57, no. 38 (2021): 4678–81. http://dx.doi.org/10.1039/d1cc01245b.

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Shapiro, Adam B., Helen Plant, Jarrod Walsh, Mark Sylvester, Jun Hu, Ning Gao, Stephania Livchak, Sharon Tentarelli, and Jason Thresher. "Discovery of ATP-Competitive Inhibitors of tRNAIle Lysidine Synthetase (TilS) by High-Throughput Screening." Journal of Biomolecular Screening 19, no. 8 (May 12, 2014): 1137–46. http://dx.doi.org/10.1177/1087057114534981.

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A novel, ultrahigh-throughput, fluorescence anisotropy–based assay was developed and used to screen a 1.4-million-sample library for compounds that compete with adenosine triphosphate (ATP) for binding to Escherichia coli tRNAIle lysidine synthetase (TilS), an essential, conserved, ATP-dependent, tRNA-modifying enzyme of bacterial pathogens. TilS modifies a cytidine base in the anticodon loop of Ile2 tRNA by attaching lysine, thereby altering codon recognition of the CAU anticodon from AUG (methionine) to AUA (isoleucine). A scintillation proximity assay for the incorporation of lysine into Ile2 tRNA was used to eliminate false positives in the initial screen resulting from detection artifacts as well as compounds competitive with the fluorescent label instead of ATP, and to measure inhibitor potencies against E. coli and Pseudomonas aeruginosa TilS isozymes. The tRNAIle substrate for P. aeruginosa TilS was identified for the first time to enable these measurements. ATP-competitive binding of inhibitors was confirmed by one-dimensional ligand-observe nuclear magnetic resonance. A preliminary structure–activity relationship is shown for two inhibitor series.

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Katari, Naresh Kumar, Rambabu Gundla, Phani Kumar Reddy, Anuradha Vanam, Aruna Talatam, Noboru Motohashi, and Rao Gollapudi. "Molecular Docking Studies of Glabrene and Human Epidermal Growth Factor Receptor Kinase." INNOSC Theranostics and Pharmacological Sciences 4, no. 1 (April 29, 2022): 38–49. http://dx.doi.org/10.36922/itps.v4i1.56.

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Background: Human epidermal growth factor receptor 2 (Her2) gene located in human chromosome17, encodes Her2 tyrosine kinase protein, and is overexpressed in breast cancer cells. Her2 is activated on phosphorylation of tyrosine by adenosine triphosphate (ATP). Nonetheless, Her2 excessively partakes in the development and prognosis of specific types of aggressive breast cancers. Therefore, Her2 inhibition therapy is primary target for the treatment of aggressive breast cancer. At present, lapatinib is one of the Food and Drug Administration approved Her2 inhibitors used in cancer therapy. In molecular docking process, glabrene with slightly higher binding energy competitively bound to the active receptor site comparable to lapatinib and ATP. Therefore, glabrene could emerge as a potential candidate for restricting Her2 overexpressed breast cancer. Objective: The present study aimed to demonstrate the inhibitory activity of glabrene, an isoflavene and xenoestrogen found in liquorice root, along with known Her2 inhibitor, lapatinib. Methods: ATP, lapatinib, and glabrene were docked on human Her2 protein 3D structure which revealed glabrene as a competitive Her2 inhibitor akin to lapatinib. Results: The docking results suggested the binding site similarities of ATP, lapatinib, and glabrene. The binding energies of docked ATP, lapatinib, and glabrene complexes with Her2 were −9.1 kcal/mol, −10.5 kcal/mol, and −11.3 kcal/mol, respectively. Conclusion: The in silico docking simulation of ATP, lapatinib, and glabrene suggested that glabrene is likewise a competitive Her2 inhibitor.

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Cuthbertson, Peter, Amal Elhage, Dena Al-Rifai, Reece A. Sophocleous, Ross J. Turner, Ashraf Aboelela, Hiwa Majed, et al. "6-Furopyridine Hexamethylene Amiloride Is a Non-Selective P2X7 Receptor Antagonist." Biomolecules 12, no. 9 (September 16, 2022): 1309. http://dx.doi.org/10.3390/biom12091309.

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P2X7 is an extracellular adenosine 5′-triphopshate (ATP)-gated cation channel present on leukocytes, where its activation induces pro-inflammatory cytokine release and ectodomain shedding of cell surface molecules. Human P2X7 can be partially inhibited by amiloride and its derivatives at micromolar concentrations. This study aimed to screen a library of compounds derived from amiloride or its derivative 5-(N,N-hexamethylene) amiloride (HMA) to identify a potential P2X7 antagonist. 6-Furopyridine HMA (6-FPHMA) was identified as a novel P2X7 antagonist and was characterized further. 6-FPHMA impaired ATP-induced dye uptake into human RPMI8226 multiple myeloma cells and human P2X7-HEK293 cells, in a concentration-dependent, non-competitive manner. Likewise, 6-FPHMA blocked ATP-induced Ca2+ fluxes in human P2X7-HEK293 cells in a concentration-dependent, non-competitive manner. 6-FPHMA inhibited ATP-induced dye uptake into human T cells, and interleukin-1β release within human blood and CD23 shedding from RPMI8226 cells. 6-FPHMA also impaired ATP-induced dye uptake into murine P2X7- and canine P2X7-HEK293 cells. However, 6-FPHMA impaired ATP-induced Ca2+ fluxes in human P2X4-HEK293 cells and non-transfected HEK293 cells, which express native P2Y1, P2Y2 and P2Y4. In conclusion, 6-FPHMA inhibits P2X7 from multiple species. Its poor selectivity excludes its use as a specific P2X7 antagonist, but further study of amiloride derivatives as P2 receptor antagonists is warranted.

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McArdell, J. E. C., C. J. Bruton, and T. Atkinson. "The isolation of a peptide from the catalytic domain of Bacillus stearothermophilus tryptophyl-tRNA synthetase. The interaction of Brown MX-5BR with tyrosyl-tRNA synthetase." Biochemical Journal 243, no. 3 (May 1, 1987): 701–7. http://dx.doi.org/10.1042/bj2430701.

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Tryptophyl-tRNA synthetase is irreversibly inactivated by Procion Brown MX-5BR with an apparent dissociation constant (KD) of 8.8 microM and maximum rate of inactivation k3 0.192 s-1. The specificity of the interaction is supported by two previously reported observations. Firstly, Brown MX-5BR inactivation of tryptophyl-tRNA synthetase is inhibited by substrates, and secondly, the animated derivative of Brown MX-5BR is a competitive inhibitor of tryptophyl-tRNA synthetase with a Ki of 2 X 10(-4) M with respect to both tryptophan and ATP. Tryptic digestion of the dye-affinity-labelled enzyme and subsequent resolution of the peptides by h.p.l.c. yielded one major dye-peptide peak. Amino acid sequence analysis resulted in the identification of the dye-binding domain centred on lysine-178. Tyrosyl-tRNA synthetase is also inactivated by Procion Brown MX-5BR, and this inactivation is prevented by ATP but not by tyrosine. The interaction of tyrosyl-tRNA synthetase with hydroxylated Brown MX-5BR exhibited non-competitive kinetics with respect to the amino acid-binding site and competitive kinetics against ATP with a Ki of 6 X 10(-6) M.

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Park, Seojeong, Soo-Yeon Hwang, Jaeho Shin, Hyunji Jo, Younghwa Na, and Youngjoo Kwon. "A chromenone analog as an ATP-competitive, DNA non-intercalative topoisomerase II catalytic inhibitor with preferences toward the alpha isoform." Chemical Communications 55, no. 85 (2019): 12857–60. http://dx.doi.org/10.1039/c9cc05524j.

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Deans, N. L., R. D. Allison, and D. L. Purich. "Steady-state kinetic mechanism of bovine brain tubulin: tyrosine ligase." Biochemical Journal 286, no. 1 (August 15, 1992): 243–51. http://dx.doi.org/10.1042/bj2860243.

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The ATP-dependent resynthesis of tubulin from tyrosine and untyrosinated tubulin was examined to establish the most probable steady-state kinetic mechanism of the tubulin: tyrosine ligase (ADP-forming). Three pair-wise sets of initial rate experiments, involving variation of two substrates pair-wise with the third substrate held at a high (but non-saturating) level, yielded convergent-line data, a behaviour that is diagnostic for sequential mechanisms. Michaelis constants were 14 microM, 1.9 microM and 17 microM for ATP, untyrosinated tubulin and L-tyrosine respectively, and the maximal velocity was 0.2 microM/min. AMP was a competitive inhibitor with respect to ATP, and a non-competitive inhibitor versus either tubulin or tyrosine. Likewise, L-dihydroxyphenylalanine acted competitively relative to tyrosine and non-competitively with respect to either ATP or tubulin. These findings directly support a random sequential mechanism. Product inhibition patterns with ADP were also consistent with this assignment; however, inhibition studies were not practical with either orthophosphate or tyrosinated tubulin because both were very weak inhibitors. Substrate protection of the enzyme against alkylation by N-ethylmaleimide and thermal inactivation, along with evidence of enzyme binding to ATP-Sepharose and tubulin-Sepharose, also supports the idea that this three-substrate enzyme reaction exhibits a random substrate addition pathway.

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Cozza, Giorgio, Andrea Bortolato, Ernesto Menta, Ennio Cavalletti, Silvano Spinelli, and Stefano Moro. "ATP Non-Competitive Ser/Thr Kinase Inhibitors as Potential Anticancer Agents." Anti-Cancer Agents in Medicinal Chemistry 9, no. 7 (September 1, 2009): 778–86. http://dx.doi.org/10.2174/187152009789056930.

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Pitman, Melissa R., Jason A. Powell, Carl Coolen, Paul A. B. Moretti, Julia R. Zebol, Duyen H. Pham, John W. Finnie, et al. "A selective ATP-competitive sphingosine kinase inhibitor demonstrates anti-cancer properties." Oncotarget 6, no. 9 (March 11, 2015): 7065–83. http://dx.doi.org/10.18632/oncotarget.3178.

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Hornakova, T., L. Springuel, J. Devreux, A. Dusa, S. N. Constantinescu, L. Knoops, and J. C. Renauld. "Oncogenic JAK1 and JAK2-activating mutations resistant to ATP-competitive inhibitors." Haematologica 96, no. 6 (March 10, 2011): 845–53. http://dx.doi.org/10.3324/haematol.2010.036350.

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