Overriding imatinib resistance with a novel ABL kinase inhibitor.

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Shah NP, Tran C, Lee FY, Chen P, Norris D, Sawyers CL

Overriding imatinib resistance with a novel ABL kinase inhibitor.

Science. 2004 Jul 16;305(5682):399-401.

PubMed ID

15256671 [ View in PubMed

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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 cells from patients with imatinib-sensitive and imatinib-resistant CML. These data illustrate how molecular insight into kinase inhibitor resistance can guide the design of second-generation targeted therapies.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Dasatinib	Breakpoint cluster region protein	Protein	Humans	Yes	Inhibitor	Details