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Allosteric inhibitors of Bcr-abl-dependent cell proliferation.

Adrian, Francisco, Ding, Qiang, Sim, Taebo, Velentza, Anastasia, Sloan, Christine, Liu, Yi, Zhang, Guobao, Hur, Wooyoung, Ding, Sheng, Manley, Paul W., Mestan, Juergen, Fabbro, Doriano and Gray, Nathanael (2006) Allosteric inhibitors of Bcr-abl-dependent cell proliferation. Nature Chemical Biology, 2 (2). pp. 95-102. ISSN 1552-4450


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.

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Date Deposited: 14 Dec 2009 14:04
Last Modified: 31 Jan 2013 01:25


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