Nature Chemical Biology 2006-02-01

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

Index: Nat. Chem. Biol. 2 , 95-102, (2006)

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Abstract

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.