Expanding the Diversity of Allosteric Bcr-Abl Inhibitors

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• 作者：Xianming Deng ; Barun Okram ; Qiang Ding ; Jianming Zhang ; Yongmun Choi ; Francisco J. Adrin ; Amy Wojciechowski ; Guobao Zhang ; Jianwei Che ; Badry Bursulaya ; Sandra W. Cowan-Jacob ; Gabriele Rummel ; Taebo S
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：October 14, 2010
• 年：2010
• 卷：53
• 期：19
• 页码：6934-6946
• 全文大小：1144K
• 年卷期：v.53,no.19(October 14, 2010)
• ISSN：1520-4804

文摘

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.