Expanding the Diversity of Allosteric Bcr-Abl Inhibitors
- Expanding the Diversity of Allosteric Bcr-Abl Inhibitors
- Xianming Deng; Barun Okram; Qiang Ding; Jianming Zhang; Yongmun Choi; Francisco J. Adrin; Amy Wojciechowski; Guobao Zhang; Jianwei Che; Badry Bursulaya; Sandra W. Cowan-Jaco; Gabriele Rummel; 심태보; Nathanael S. Gray
- Issue Date
- Journal of medicinal chemistry
- VOL 53, NO 19, 6934-6946
- 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.
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