714962-04-6Relevant academic research and scientific papers
ALLOSTERIC BCR-ABL PROTEOLYSIS TARGETING CHIMERIC COMPOUNDS
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Page/Page column 174; 176, (2020/10/18)
The present invention includes novel compounds and methods for preventing or treating diseases associated with and/or caused by overexpression and/or uncontrolled activation of a tyrosine kinase in a subject in need thereof. In certain embodiments, the compounds of the present invention include an allosteric tyrosine kinase inhibitor, a linker, and a ubiquitin ligase binder. The methods of the present invention include administering to the subject an pharmaceutically effective amount of at least one compound of the invention.
LOW MOLECULAR MYRISTIC ACID ESTER INHIBITOR OF BCR-ABL AND METHOD OF APPLICATION THEREOF
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Paragraph 0149, (2016/10/08)
PROBLEM TO BE SOLVED: To provide a compound useful for treatment of diseases to which one or more kinase, especially a kinase inhibiting a Bcr-abl wild type and one or more Bcr-abl mutant relate, especially diseases to which a fusion type tyrosine kinase
Direct binding assay for the detection of type IV allosteric inhibitors of Abl
Schneider, Ralf,Becker, Christian,Simard, Jeffrey R.,Getlik, Matthaeus,Bohlke, Nina,Janning, Petra,Rauh, Daniel
supporting information; experimental part, p. 9138 - 9141 (2012/07/14)
Abelson (Abl) tyrosine kinase is an important cellular enzyme that is rendered constitutively active in the breakpoint cluster region (BCR)-Abl fusion protein, contributing to several forms of leukemia. Although inhibiting BCR-Abl activity with imatinib shows great clinical success, many patients acquire secondary mutations that result in resistance to imatinib. Second-generation inhibitors such as dasatinib and nilotinib can overcome the majority of these mutations but fail to treat patients with an especially prevalent T315I mutation at the gatekeeper position of the kinase domain. However, a combination of nilotinib with an allosteric type IV inhibitor was recently shown to overcome this clinically relevant point mutation. In this study, we present the development of a direct binding assay that enables the straightforward detection of allosteric inhibitors which bind within the myristate pocket of Abl. The assay is amenable to high-throughput screening and exclusively detects the binding of ligands to this unique allosteric site.
Expanding the diversity of allosteric Bcr-Abl inhibitors
Deng, Xianming,Okram, Barun,Ding, Qiang,Zhang, Jianming,Choi, Yongmun,Adrián, Francisco J.,Wojciechowski, Amy,Zhang, Guobao,Che, Jianwei,Bursulaya, Badry,Cowan-Jacob, Sandra W.,Rummel, Gabriele,Sim, Taebo,Gray, Nathanael S.
experimental part, p. 6934 - 6946 (2010/12/25)
Inhibition of Bcr-Abl kinase activity by imatinib for the treatment of chronic myeloid leukemia (CML) currently serves as the paradigm for targeting dominant oncogenes with small molecules. We recently reported the discovery of GNF-2 (1) and GNF-5 (2) as selective non-ATP competitive inhibitors of cellular Bcr-Abl kinase activity that target the myristate binding site. Here, we used cell-based structure-activity relationships to guide the optimization and diversification of ligands that are capable of binding to the myristate binding site and rationalize the findings based upon an Abl-compound 1 cocrystal. We elucidate the structure-activity relationships required to obtain potent antiproliferative activity against Bcr-Abl transformed cells and report the discovery of new compounds (5g, 5h, 6a, 14d, and 21j-I) that display improved potency or pharmacological properties. This work demonstrates that a variety of structures can effectively target the Bcr-Abl myristate binding site and provides new leads for developing drugs that can target this binding site.
Binding or bending: Distinction of allosteric abl kinase agonists from antagonists by an NMR-based conformational assay
Jahnke, Wolfgang,Grotzfeld, Robert M.,Pelle, Xavier,Strauss, Andre,Fendrich, Gabriele,Cowan-Jacob, Sandra W.,Cotesta, Simona,Fabbro, Doriano,Furet, Pascal,Mestan, Juergen,Marzinzik, Andreas L.
supporting information; experimental part, p. 7043 - 7048 (2010/07/08)
Allosteric inhibitors of Bcr-Abl have emerged as a novel therapeutic option for the treatment of CML. Using fragment-based screening, a search for novel Abl inhibitors that bind to the myristate pocket was carried out. Here we show that not all myristate ligands are functional inhibitors, but that the conformational state of C-terminal helix-I is a structural determinant for functional activity. We present an NMR-based conformational assay to monitor the conformation of this crucial helix-I and show that myristate ligands that bend helix-I are functional antagonists, whereas ligands that bind to the myristate pocket but do not induce this conformational change are kinase agonists. Activation of c-Abl by allosteric agonists has been confirmed in a biochemical assay.
