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
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.
- Biological Chemistry Department, Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
- Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
- 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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