778275-58-4Relevant academic research and scientific papers
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.
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.
supporting information; 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.
