Overriding imatinib resistance with a novel ABL kinase inhibitor Academic Article uri icon

Overview

MeSH Major

  • Antineoplastic Agents
  • Fusion Proteins, bcr-abl
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive
  • Piperazines
  • Pyrimidines
  • Thiazoles

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.

publication date

  • July 16, 2004

Research

keywords

  • Academic Article

Identity

Language

  • eng

Digital Object Identifier (DOI)

  • 10.1126/science.1099480

PubMed ID

  • 15256671

Additional Document Info

start page

  • 399

end page

  • 401

volume

  • 305

number

  • 5682