Expanding the diversity of allosteric Bcr-Abl inhibitors

Xianming Deng, Barun Okram, Qiang Ding, Jianming Zhang, Yongmun Choi, Francisco J. Adrián, Amy Wojciechowski, Guobao Zhang, Jianwei Che, Badry Bursulaya, Sandra W. Cowan-Jacob, Gabriele Rummel, Taebo Sim, Nathanael S. Gray

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)6934-6946
Number of pages13
JournalJournal of Medicinal Chemistry
Volume53
Issue number19
DOIs
Publication statusPublished - 2010 Oct 14

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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  • Cite this

    Deng, X., Okram, B., Ding, Q., Zhang, J., Choi, Y., Adrián, F. J., Wojciechowski, A., Zhang, G., Che, J., Bursulaya, B., Cowan-Jacob, S. W., Rummel, G., Sim, T., & Gray, N. S. (2010). Expanding the diversity of allosteric Bcr-Abl inhibitors. Journal of Medicinal Chemistry, 53(19), 6934-6946. https://doi.org/10.1021/jm100555f