期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 103, 期 24, 页码 9244-9249出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0600001103
关键词
kinase inhibitors; imatinib; combination chemotherapy; chronic myelogenous leukemia
资金
- NCI NIH HHS [P30 CA008748, P01 CA064593] Funding Source: Medline
Mutation in the ABL kinase domain is the principal mechanism of imatinib resistance in patients with chronic myelogenous leukemia. Many mutations favor active kinase conformations that preclude imatinib binding. Because the active forms of ABL and SRC resemble one another, we tested two dual SRC-ABL kinase inhibitors, AP23464 and PD166326, against 58 imatinib-resistant (IMR) BCR/ABL kinase variants. Both compounds potently inhibit most IMR variants, and in vitro drug selection demonstrates that active (AP23464) and open (PD166326) conformation-specific compounds are less susceptible to resistance than imatinib. Combinations of inhibitors suppressed essentially all resistance mutations, with the notable exception of T3151. Guided by mutagenesis studies and molecular modeling, we designed a series of AP23464 analogues to target T3151. The analogue AP23846 inhibited both native and T3151 variants of BCR/ABL with submicromolar potency but showed nonspecific cellular toxicity. Our data illustrate how conformational dynamics of the ABL kinase accounts for the activity of dual SRC-ABL inhibitors against IMR-mutants and provides a rationale for combining conformation specific inhibitors to suppress resistance.
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