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Articles de revues sur le sujet « Dual-warhead »

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Auteur : Grafiati
Publié le 14 mars 2023

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1

Kim, Jisu, Ching-Hsuan Tung et Yongdoo Choi. « Smart dual-functional warhead for folate receptor-specific activatable imaging and photodynamic therapy ». Chem. Commun. 50, no 73 (2014) : 10600–10603. http://dx.doi.org/10.1039/c4cc04166f.

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Świderska, Karolina, Anna Szlachcic, Łukasz Opaliński, Małgorzata Zakrzewska et Jacek Otlewski. « FGF2 Dual Warhead Conjugate with Monomethyl Auristatin E and α-Amanitin Displays a Cytotoxic Effect towards Cancer Cells Overproducing FGF Receptor 1 ». International Journal of Molecular Sciences 19, no 7 (19 juillet 2018) : 2098. http://dx.doi.org/10.3390/ijms19072098.

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In the rapidly developing field of targeted cancer therapy there is growing interest towards therapeutics combining two or more compounds to achieve synergistic action and minimize the chance of cancer resistance to treatment. We developed a fibroblast growth factor 2 (FGF2)-conjugate bearing two cytotoxic drugs with independent mode of action: α-amanitin and monomethyl auristatin E. Drugs are covalently attached to the targeting protein in a site-specific manner via maleimide-thiol conjugation and Cu(I)-catalyzed alkyne-azide cycloaddition. The dual warhead conjugate binds to FGF receptor 1 (FGFR1) and utilizes receptor-mediated endocytosis for selective internalization into cancer cells with FGFR1. The developed conjugate displays high cytotoxicity towards all tested FGFR1-positive cell lines. Most importantly, the improved cytotoxic effect of both drugs is observed for lung cancer cell line NCI-H446. The single drug-FGF2 conjugates have no impact on the viability of NCI-H446 cells, whereas the dual warhead-FGF2 conjugate selectively and efficiently kills these FGFR1 positive cancer cells. Due to the diversified mode of action the dual warhead-FGF2 conjugate may overcome the potential acquired resistance of FGFR1-overproducing cancer cells towards single cytotoxic drugs.
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Johns, Brian A., et Carl R. Johnson. « Scaffolded bis-azasugars : A dual warhead approach to glycosidase inhibition ». Tetrahedron Letters 39, no 8 (février 1998) : 749–52. http://dx.doi.org/10.1016/s0040-4039(97)10616-5.

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Brouwer, Arwin J., Natalia Herrero Álvarez, Adriano Ciaffoni, Helmus van de Langemheen et Rob M. J. Liskamp. « Proteasome inhibition by new dual warhead containing peptido vinyl sulfonyl fluorides ». Bioorganic & ; Medicinal Chemistry 24, no 16 (août 2016) : 3429–35. http://dx.doi.org/10.1016/j.bmc.2016.05.042.

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JOHNS, B. A., et C. R. JOHNSON. « ChemInform Abstract : Scaffolded Bis-azasugars : A Dual Warhead Approach to Glycosidase Inhibition. » ChemInform 29, no 19 (22 juin 2010) : no. http://dx.doi.org/10.1002/chin.199819222.

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Bhattacharyya, Soumalya, Mangili Venkateswarulu, Jagabandhu Sahoo, Ennio Zangrando, Mrinmoy De et Partha Sarathi Mukherjee. « Self-Assembled PtII8 Metallosupramolecular Tubular Cage as Dual Warhead Antibacterial Agent in Water ». Inorganic Chemistry 59, no 17 (7 août 2020) : 12690–99. http://dx.doi.org/10.1021/acs.inorgchem.0c01777.

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Astrain-Redin, Nora, Irene Talavera, Esther Moreno, María J. Ramírez, Nuria Martínez-Sáez, Ignacio Encío, Arun K. Sharma, Carmen Sanmartín et Daniel Plano. « Seleno-Analogs of Scaffolds Resembling Natural Products a Novel Warhead toward Dual Compounds ». Antioxidants 12, no 1 (6 janvier 2023) : 139. http://dx.doi.org/10.3390/antiox12010139.

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Nowadays, oxidative cell damage is one of the common features of cancer and Alzheimer’s disease (AD), and Se-containing molecules, such as ebselen, which has demonstrated strong antioxidant activity, have demonstrated well-established preventive effects against both diseases. In this study, a total of 39 Se-derivatives were synthesized, purified, and spectroscopically characterized by NMR. Antioxidant ability was tested using the DPPH assay, while antiproliferative activity was screened in breast, lung, prostate, and colorectal cancer cell lines. In addition, as a first approach to evaluate their potential anti-Alzheimer activity, the in vitro acetylcholinesterase inhibition (AChEI) was tested. Regarding antioxidant properties, compound 13a showed concentration- and time-dependent radical scavenging activity. Additionally, compounds 14a and 17a showed high activity in the melanoma and ovarian cancer cell lines, with LD50 values below 9.2 µM. Interestingly, in the AChEI test, compound 14a showed almost identical inhibitory activity to galantamine along with a 3-fold higher in vitro BBB permeation (Pe = 36.92 × 10−6 cm/s). Molecular dynamics simulations of the aspirin derivatives (14a and 14b) confirm the importance of the allylic group instead of the propargyl one. Altogether, it is concluded that some of these newly synthesized Se-derivatives, such as 14a, might become very promising candidates to treat both cancer and AD.
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Shi, Yun Bo, Sheng Fei Dong et Zhi Jun Zhou. « Study on Measurement Method of Dynamic Linearity for High G Micro Accelerometer ». Key Engineering Materials 609-610 (avril 2014) : 908–13. http://dx.doi.org/10.4028/www.scientific.net/kem.609-610.908.

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Linearity, dynamic linearity particularly, is an important parameter in measuring the performance of an accelerometer. The Hopkinson bar has been widely used in calibration of high g accelerometer and other high overloading conditions. Based on one-dimension stress wave theory and superposition theory of elastic waves, designed a Dual Warhead Hopkinson bar to demarcate the dynamic linear parameters of high g micro accelerometer accurately. A finite element model for Hopkinson bar calibration system was created, ANSYS/LS-DYNA was employed to simulate the operation process of Hopkinson bar, and the effects of the projectile's materials, adjustment pads materials and thickness on the acceleration waveform were found.
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Chinthakindi, Praveen K., Kimberleigh B. Govender, A. Sanjeeva Kumar, Hendrik G. Kruger, Thavendran Govender, Tricia Naicker et Per I. Arvidsson. « A Synthesis of “Dual Warhead” β-Aryl Ethenesulfonyl Fluorides and One-Pot Reaction to β-Sultams ». Organic Letters 19, no 3 (11 janvier 2017) : 480–83. http://dx.doi.org/10.1021/acs.orglett.6b03634.

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Vineberg, Jacob G., Edison S. Zuniga, Anushree Kamath, Ying-Jen Chen, Joshua D. Seitz et Iwao Ojima. « Design, Synthesis, and Biological Evaluations of Tumor-Targeting Dual-Warhead Conjugates for a Taxoid–Camptothecin Combination Chemotherapy ». Journal of Medicinal Chemistry 57, no 13 (19 juin 2014) : 5777–91. http://dx.doi.org/10.1021/jm500631u.

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Mohapatra, Saswat, Abhijit Saha, Prasenjit Mondal, Batakrishna Jana, Subhajit Ghosh, Atanu Biswas et Surajit Ghosh. « Synergistic Anticancer Effect of Peptide-Docetaxel Nanoassembly Targeted to Tubulin : Toward Development of Dual Warhead Containing Nanomedicine ». Advanced Healthcare Materials 6, no 2 (26 octobre 2016) : 1600718. http://dx.doi.org/10.1002/adhm.201600718.

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Krzyscik, Mateusz Adam, Łukasz Opaliński et Jacek Otlewski. « Novel Method for Preparation of Site-Specific, Stoichiometric-Controlled Dual Warhead Conjugate of FGF2 via Dimerization Employing Sortase A-Mediated Ligation ». Molecular Pharmaceutics 16, no 8 (17 juin 2019) : 3588–99. http://dx.doi.org/10.1021/acs.molpharmaceut.9b00434.

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Shi, Yunbo, Zhicai Yang, Zongmin Ma, Huiliang Cao, Zhiwei Kou, Dan Zhi, Yanxiang Chen, Hengzhen Feng et Jun Liu. « The Development of a Dual-Warhead Impact System for Dynamic Linearity Measurement of a High-g Micro-Electro-Mechanical-Systems (MEMS) Accelerometer ». Sensors 16, no 6 (8 juin 2016) : 840. http://dx.doi.org/10.3390/s16060840.

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Thiyagarajan, Durairaj, Sudeep Goswami, Chirantan Kar, Gopal Das et Aiyagari Ramesh. « A prospective antibacterial for drug-resistant pathogens : a dual warhead amphiphile designed to track interactions and kill pathogenic bacteria by membrane damage and cellular DNA cleavage ». Chemical Communications 50, no 56 (2014) : 7434. http://dx.doi.org/10.1039/c4cc02354d.

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Ailawadhi, Sikander, Asher Alban Akmal Chanan-Khan, Jennifer Layton Peterson, Jarrod Longcor, Katherine Oliver, Matthew Francis Brown, John Friend et Damian Jonathan Green. « Treatment free remission (TFR) and overall response rate (ORR) results in patients with relapsed/refractory Waldenstrom’s macroglobulinemia (WM) treated with CLR 131. » Journal of Clinical Oncology 39, no 15_suppl (20 mai 2021) : 7561. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.7561.

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7561 Background: Phospholipid ethers (PLE) provide a novel mechanism to specifically target tumor cells leveraging high lipid raft content in their cell membranes. PLE/phospholipid drug conjugates are specifically designed to have high affinity to lipid rafts which upon binding results in trans-membrane flipping with the ability to deliver an attached warhead directly to the cytosol. CLR 131 (I-131-CLR1404) is a novel PLE molecule armed with I-131 resulting in targeted tumor cell radiotherapy which is being examined in relapsed or refractory WM through an open-label, Phase 2 trial, CLOVER-1 (NCT02952508). Methods: The primary objective of this study is to determine the efficacy and safety of CLR 131 in select B-cell malignancies. Eligibility criteria for WM pts include receipt of at least 2 prior treatment regimens unless ineligible to receive standard agents and have measurable disease: either IgM or extramedullary disease. CLR 131 is administered in up to 4 IV infusions (15-20 min) over 3 months. Adverse events (AEs) are graded by NCI-CTCAE v4.03; responses are assessed by the VIth WM Criteria for Response Assessment [Owen 2013]. Results: 6 pts with WM were enrolled in the study with data current as of 8 Jan 2021. The median age was 69 (range 54-81) with 4 females and 2 males who had a median of 2 prior regimens (range 1-5) and received a mean total body dose of 92.76 mCi CLR 131. 3 of 6 patients were MYD88 wild type (WT) of which 2 were dual WT (MYD88 WT & CXCR4 WT). The overall response rate (ORR) was 100% and the major response rate (MRR) was 83%, including 1 pt with a CR, 4 PR, and 1 MR. For those pts who were dual WT, the MRR was 100% and 1 pt who was MYD88 WT (CXCR4 is unknown) had a complete response. The median time to initial response was 48 days. Median duration of response (DOR) and treatment free remission (TFR) have not been reached; ongoing mean DOR is 335 days and mean TFR is 384 days. 100% of MYD88 WT patients have exceeded 6.5 months of follow up with average TFR of 18.1 months. The primary treatment emergent AEs in pts with WM included fatigue and cytopenias, in line with prior experience with CLR 131 in other B-cell malignancies. The most commonly observed cytopenias included Grade 3 or 4 thrombocytopenia (100%), neutropenia (83%), anaemia (66%) and decreased white blood cell count (33%). Of note, no cases of bleeding or febrile neutropenia were observed. Conclusions: Initial results for CLR 131 show efficacy across multiple WM patient genotypes including dual WT patients with durable DOR and TFR after 2 to 4 infusions. CLR 131 represents a novel and promising approach to the treatment of MYD88 WT patients who have a historical median time to progression of 1.3 years. These encouraging data led to the pivotal global CLOVER-WaM trial (N=50) in WM patients who have failed or had a suboptimal response to a Bruton Tyrosine Kinase inhibitor. CLOVER-WaM is currently enrolling. Clinical trial information: NCT02952508.
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Manda, Sudhakar, Na Keum Lee, Dong-Chan Oh et Jeeyeon Lee. « Design, Synthesis, and Biological Evaluation of Proteolysis Targeting Chimeras (PROTACs) for the Dual Degradation of IGF-1R and Src ». Molecules 25, no 8 (23 avril 2020) : 1948. http://dx.doi.org/10.3390/molecules25081948.

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A focused PROTAC library was developed to degrade both IGF-1R and Src proteins, which are associated with various cancers. PROTACs with IGF-1R and Src degradation potentials were synthesized by tethering different inhibitor warhead units and the E3 ligase (CRBN) recruiting-pomalidomide with various linkers. The designed PROTACs 12a–b inhibited the proliferation and migration of MCF7 and A549 cancer cells with low micromolar potency (1–5 μM) in various cellular assays.
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Chen, Xiaojuan, Huiliang Li, Qianmeng Lin, Shuyan Dai, Sitong Yue, Lingzhi Qu, Maoyu Li et al. « Structure-based design of a dual-warhead covalent inhibitor of FGFR4 ». Communications Chemistry 5, no 1 (17 mars 2022). http://dx.doi.org/10.1038/s42004-022-00657-9.

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AbstractThe fibroblast growth factor 19 (FGF19)/fibroblast growth factor receptor 4 (FGFR4) signaling pathways play critical roles in a variety of cancers, such as hepatocellular carcinoma (HCC). FGFR4 is recognized as a promising target to treat HCC. Currently, all FGFR covalent inhibitors target one of the two cysteines (Cys477 and Cys552). Here, we designed and synthesized a dual-warhead covalent FGFR4 inhibitor, CXF-009, targeting Cys477 and Cys552 of FGFR4. We report the cocrystal structure of FGFR4 with CXF-009, which exhibits a dual-warhead covalent binding mode. CXF-009 exhibited stronger selectivity for FGFR4 than FGFR1-3 and other kinases. CXF-009 can also potently inhibit the single cystine mutants, FGFR4(C477A) and FGFR4(C552A), of FGFR4. In summary, our study provides a dual-warhead covalent FGFR4 inhibitor that can covalently target two cysteines of FGFR4. CXF-009, to our knowledge, is the first reported inhibitor that forms dual-warhead covalent bonds with two cysteine residues in FGFR4. CXF-009 also has the potential to overcome drug induced resistant FGFR4 mutations and might serve as a lead compound for future anticancer drug discovery.
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Guo, Xiao-Jun, et He-Ming Wen. « Performance Analysis and Optimization of a Dual Warhead System ». International Journal of Nonlinear Sciences and Numerical Simulation 13, no 1 (1 janvier 2012). http://dx.doi.org/10.1515/ijnsns-2011-0100.

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AbstractIn modern warfare earth penetrating weapons are often used to defeat enemy’s hardened and deeply buried targets such as aircraft shelters and bunkers. A dual warhead system (DWS) is one of such weapons composed of a forward shaped charge (FSC) and a following through warhead (FTW). In this paper, an analytical model is first proposed to analyze the penetration of an FTW into concrete targets with pre-drilled holes and a DWS is then optimized in order to achieve its best penetration performance. The effects of various parameters on the performance of a dual warhead system penetrating a concrete target are delineated. It transpires that the present model predictions are in good agreement with available experimental data and that the results obtained may be useful for designing such weapon systems.
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Guo, Xiao-Jun, et He-Ming Wen. « Performance Analysis and Optimization of a Dual Warhead System ». International Journal of Nonlinear Sciences and Numerical Simulation 13, no 1 (1 janvier 2012). http://dx.doi.org/10.1515/ijnsns-2011-100.

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AbstractIn modern warfare earth penetrating weapons are often used to defeat enemy’s hardened and deeply buried targets such as aircraft shelters and bunkers. A dual warhead system (DWS) is one of such weapons composed of a forward shaped charge (FSC) and a following through warhead (FTW). In this paper, an analytical model is first proposed to analyze the penetration of an FTW into concrete targets with pre-drilled holes and a DWS is then optimized in order to achieve its best penetration performance. The effects of various parameters on the performance of a dual warhead system penetrating a concrete target are delineated. It transpires that the present model predictions are in good agreement with available experimental data and that the results obtained may be useful for designing such weapon systems.
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Chen, Xiaojuan, Huiliang Li, Qianmeng Lin, Shuyan Dai, Sitong Yue, Lingzhi Qu, Maoyu Li et al. « Author Correction : Structure-based design of a dual-warhead covalent inhibitor of FGFR4 ». Communications Chemistry 5, no 1 (14 avril 2022). http://dx.doi.org/10.1038/s42004-022-00672-w.

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21

Moreira, Wilfried, Sridhar Santhanakrishnan, Brian W. Dymock et Thomas Dick. « Bortezomib Warhead-Switch Confers Dual Activity against Mycobacterial Caseinolytic Protease and Proteasome and Selectivity against Human Proteasome ». Frontiers in Microbiology 8 (27 avril 2017). http://dx.doi.org/10.3389/fmicb.2017.00746.

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Cheng, Lin, Shichao Zhou, Shaoqing Zhou, Kaixuan Shi, Yan Cheng, Mei-Chun Cai, Kaiyan Ye et al. « Dual inhibition of CDK12/CDK13 targets both tumor and immune cells in ovarian cancer ». Cancer Research, 20 juillet 2022. http://dx.doi.org/10.1158/0008-5472.can-22-0222.

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Abstract Therapeutic perturbation of cyclin-dependent kinase 12 (CDK12) is proposed to have pleiotropic effects in ovarian cancer, including direct cytotoxicity against tumor cells and indirect induction of immunogenicity that confer synthetic sensitivity to immune-based treatment. However, formal testing of this hypothesis has been hindered by an insufficient mechanistic understanding of CDK12 and its close homolog CDK13, as well as generally unfavorable pharmacokinetics of available CDK12/CDK13 covalent inhibitors. In this study, we employed an innovative arsenous warhead modality to develop an orally bioavailable CDK12/CDK13 covalent compound. The dual CDK12/CDK13 inhibitor ZSQ836 exerted potent anticancer activity in cell culture and mouse models and induced transcriptional reprogramming, including downregulation of DNA damage response genes. CDK12 and CDK13 were both ubiquitously expressed in primary and metastatic ovarian cancer, and the two kinases performed independent and synergistic functions to promote tumorigenicity. Unexpectedly, although ZSQ836 triggered genomic instability in malignant cells, it counterintuitively impaired lymphocytic infiltration in neoplastic lesions by interfering with T cell proliferation and activation. These findings highlight the Janus-faced effects of dual CDK12/CDK13 inhibitors by simultaneously suppressing tumor and immune cells, offering valuable insights into the future direction of drug discovery to pharmacologically target CDK12.
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Mohapatra, Saswat, Abhijit Saha, Prasenjit Mondal, Batakrishna Jana, Subhajit Ghosh, Atanu Biswas et Surajit Ghosh. « Antimitoic Peptides : Synergistic Anticancer Effect of Peptide-Docetaxel Nanoassembly Targeted to Tubulin : Toward Development of Dual Warhead Containing Nanomedicine (Adv. Healthcare Mater. 2/2017) ». Advanced Healthcare Materials 6, no 2 (janvier 2017). http://dx.doi.org/10.1002/adhm.201770011.

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