Overriding imatinib resistance with a novel ABL kinase inhibitor

Neil P Shah; Chris Tran; Francis Y Lee; Ping Chen; Derek Norris; Charles L Sawyers

doi:10.1126/science.1099480

Overriding imatinib resistance with a novel ABL kinase inhibitor

Science. 2004 Jul 16;305(5682):399-401. doi: 10.1126/science.1099480.

Authors

Neil P Shah¹, Chris Tran, Francis Y Lee, Ping Chen, Derek Norris, Charles L Sawyers

Affiliation

¹ Division of Hematology and Oncology, Department of Medicine, The David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA.

PMID: 15256671
DOI: 10.1126/science.1099480

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 types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

MeSH terms

Amino Acid Substitution
Animals
Antineoplastic Agents / metabolism
Antineoplastic Agents / pharmacology*
Antineoplastic Agents / therapeutic use
Benzamides
Binding Sites
Cell Division / drug effects
Cell Line
Clinical Trials, Phase I as Topic
Dasatinib
Drug Resistance, Neoplasm
Enzyme Inhibitors / metabolism
Enzyme Inhibitors / pharmacology
Enzyme Inhibitors / therapeutic use
Fusion Proteins, bcr-abl / antagonists & inhibitors*
Fusion Proteins, bcr-abl / chemistry
Fusion Proteins, bcr-abl / genetics
Fusion Proteins, bcr-abl / metabolism
Hematopoietic Stem Cells / drug effects
Humans
Imatinib Mesylate
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
Mice
Mice, SCID
Mutation
Piperazines / pharmacology*
Piperazines / therapeutic use
Protein Conformation
Pyrimidines / metabolism
Pyrimidines / pharmacology*
Pyrimidines / therapeutic use
Thiazoles / metabolism
Thiazoles / pharmacology*
Thiazoles / therapeutic use
Transfection

Substances

Antineoplastic Agents
Benzamides
Enzyme Inhibitors
Piperazines
Pyrimidines
Thiazoles
abl-bcr fusion protein, human
Imatinib Mesylate
Fusion Proteins, bcr-abl
Dasatinib