Journal
CHEMICAL BIOLOGY & DRUG DESIGN
Volume 75, Issue 2, Pages 223-227Publisher
WILEY
DOI: 10.1111/j.1747-0285.2009.00911.x
Keywords
Tyrosine kinase inhibitors; BCR; ABL; Gatekeeper mutant; Chronic myeloid leukemia; Drug resistance and Type II kinase inhibitor
Funding
- NIH
- NIH Roadmap for Medical Research
- Leukemia and Lymphoma Society
- Burroughs Wellcome Fund
- Thomas Anthony Pappas Charitable Foundation
Ask authors/readers for more resources
Mutation in the ABL kinase domain is the principal mechanism of imatinib resistance in patients with chronic myelogenous leukaemia. The second generation BCR/ABL inhibitors nilotinib and dasatinib effectively inhibit most imatinib resistance variants, but are ineffective against the gatekeeper mutant, T315I. Gatekeeper mutation activates the kinase by stabilizing the hydrophobic spine. Here, we describe that the rationally designed compound AP24163 can inhibit native and gatekeeper mutants of the BCR/ABL kinase. Structural modelling suggests that AP24163 affects the flexibility of the P-loop and destabilizes the active conformation by disrupting the hydrophobic spine. In vitro screening for drug resistance identified clones with compound mutations involving both the P-loop and T315I. Our studies provide structural insights for the design of inhibitors against the gatekeeper mutant and suggest that up-front combination therapy may be required to prevent the emergence of compound-resistant mutations.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available