Article abstract


Nature Chemical Biology 2, 95 - 102 (2006)
Published online: 15 January 2006 | doi:10.1038/nchembio760

Allosteric inhibitors of Bcr-abl–dependent cell proliferation

Francisco J Adrián1, Qiang Ding1, Taebo Sim1, Anastasia Velentza1, Christine Sloan1, Yi Liu1, Guobao Zhang1, Wooyoung Hur1, Sheng Ding2, Paul Manley3, Jürgen Mestan3, Doriano Fabbro3 & Nathanael S Gray1


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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  1. Biological Chemistry Department, Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
  2. Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
  3. Oncology Research, Novartis Institutes for Biomedical Research, CH-4002 Basel, Switzerland.

Correspondence to: Nathanael S Gray1 e-mail: ngray@gnf.org



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