Allosteric inhibitors of Bcr-abl-dependent cell proliferation

Francisco J. Adrián, Qiang Ding, Taebo Sim, Anastasia Velentza, Christine Sloan, Yi Liu, Guobao Zhang, Wooyoung Hur, Sheng Ding, Paul Manley, Jürgen Mestan, Doriano Fabbro, Nathanael S. Gray

Research output: Contribution to journalArticlepeer-review

327 Citations (Scopus)


Chronic myelogenous leukemia (CML) is a myeloproliferative disorder characterized at the molecular level by the expression of Bcr-abl, a 210-kDa fusion protein with deregulated tyrosine kinase activity. Encouraged by the clinical validation of Bcr-abl as the target for the treatment of CML by imatinib, we sought to identify pharmacological agents that could target this kinase by a distinct mechanism. We report the discovery of a new class of Bcr-abl inhibitors using an unbiased differential cytotoxicity screen of a combinatorial kinase-directed heterocycle library. Compounds in this class (exemplified by GNF-2) show exclusive antiproliferative activity toward Bcr-abl-transformed cells, with potencies similar to imatinib, while showing no inhibition of the kinase activity of full-length or catalytic domain of c-abl. We propose that this new class of compounds inhibits Bcr-abl kinase activity through an allosteric non-ATP competitive mechanism.

Original languageEnglish
Pages (from-to)95-102
Number of pages8
JournalNature Chemical Biology
Issue number2
Publication statusPublished - 2006 Feb

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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