Overriding Imatinib Resistance with a Novel ABL Kinase Inhibitor
Howard Hughes Medical Institute · University of California, Los Angeles · +1 more institution
Abstract
Resistance to the ABL kinase inhibitor imatinib (STI571 or Gleevec) in chronic myeloid leukemia (CML) occurs through selection for tumor cells harboring BCR-ABL kinase domain point mutations that interfere with drug binding. Crystallographic studies predict that most imatinib-resistant mutants should remain sensitive to inhibitors that bind ABL with less stringent conformational requirements. BMS-354825 is an orally bioavailable ABL kinase inhibitor with two-log increased potency relative to imatinib that retains activity against 14 of 15 imatinib-resistant BCR-ABL mutants. BMS-354825 prolongs survival of mice with BCR-ABL-driven disease and inhibits proliferation of BCR-ABL-positive bone marrow progenitor…
Citation impact
- FWCI
- 75.59
- Percentile
- 100%
- References
- 20
Authors
6- NPNeil P. Shah
Howard Hughes Medical Institute, University of California, Los Angeles, Bristol-Myers Squibb (United States)
- CTChris Tran
Howard Hughes Medical Institute, University of California, Los Angeles, Bristol-Myers Squibb (United States)
- FYFrancis Y. Lee
Howard Hughes Medical Institute, University of California, Los Angeles, Bristol-Myers Squibb (United States)
- PCPing Chen
Howard Hughes Medical Institute, University of California, Los Angeles, Bristol-Myers Squibb (United States)
- DNDerek Norris
Howard Hughes Medical Institute, University of California, Los Angeles, Bristol-Myers Squibb (United States)
Topics & keywords
- Imatinib
- Cancer research
- ABL
- Protein kinase domain
- Myeloid leukemia
- Imatinib mesylate
- Nilotinib
- Kinase
- Good health and well-being