Gleevec: The Sequel

Science's STKE  20 Jul 2004:
Vol. 2004, Issue 242, pp. tw263-TW263
DOI: 10.1126/stke.2422004TW263

The tyrosine kinase inhibitor imatinib (Gleevec) is now a frontline treatment for chronic myelogenous leukemia (CML). As with most cancer therapies, however, a subset of patients develop resistance to imatinib, a problem that has been traced to the acquisition of specific mutations in the oncogenic BCR-ABL kinase targeted by the drug. Guided by these mutational data as well as crystallographic data detailing how imatinib binds to the ABL kinase domain, Shah et al. have isolated a new tyrosine kinase inhibitor that appears to have all of the favorable characteristics of imatinib--and more. Preclinical studies of this second-generation drug (an orally available thiazolecarboxamide) in a mouse model and in cultured bone marrow cells from CML patients indicate that it is more potent than imatinib and, importantly, retains activity against the majority of imatinib-resistant BCR-ABL mutants without significant toxicity.

N. P. Shah, C. Tran, F. Y. Lee, P. Chen, D. Norris, C. L. Sawyers, Overriding imatinib resistance with a novel ABL kinase inhibitor. Science 305, 399-401 (2004). [Abstract] [Full Text]