Publication Date:
2004-07-17
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shah, Neil P -- Tran, Chris -- Lee, Francis Y -- Chen, Ping -- Norris, Derek -- Sawyers, Charles L -- New York, N.Y. -- Science. 2004 Jul 16;305(5682):399-401.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Hematology and Oncology, Department of Medicine, The David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/15256671" target="_blank"〉PubMed〈/a〉
Keywords:
Amino Acid Substitution
;
Animals
;
Antineoplastic Agents/metabolism/*pharmacology/therapeutic use
;
Benzamides
;
Binding Sites
;
Cell Division/drug effects
;
Cell Line
;
Clinical Trials, Phase I as Topic
;
Dasatinib
;
Drug Resistance, Neoplasm
;
Enzyme Inhibitors/metabolism/pharmacology/therapeutic use
;
Fusion Proteins, bcr-abl/*antagonists & inhibitors/chemistry/genetics/metabolism
;
Hematopoietic Stem Cells/drug effects
;
Humans
;
Imatinib Mesylate
;
Leukemia, Myelogenous, Chronic, BCR-ABL Positive/*drug therapy
;
Mice
;
Mice, SCID
;
Mutation
;
Piperazines/*pharmacology/therapeutic use
;
Protein Conformation
;
Pyrimidines/metabolism/*pharmacology/therapeutic use
;
Thiazoles/metabolism/*pharmacology/therapeutic use
;
Transfection
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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