Overriding Imatinib Resistance with a Novel ABL Kinase Inhibitor

TLDR

Imatinib resistance in CML is driven by BCR‑ABL point mutations that block drug binding, yet crystallographic analysis predicts many of these mutants remain susceptible to inhibitors that bind ABL with less stringent conformational requirements. BMS‑354825, an orally bioavailable ABL kinase inhibitor, is 100‑fold more potent than imatinib, retains activity against 14 of 15 resistant mutants, prolongs survival in BCR‑ABL‑driven mice, and inhibits proliferation of patient‑derived BCR‑ABL‑positive progenitors, illustrating that structure‑guided design can overcome resistance.

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.