title: Overriding imatinib resistance with a novel ABL kinase inhibitor.
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.
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, The David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA.
authors.forename: Neil P
authors.initials: NP
authors.lastname: Shah
authors.forename: Chris
authors.initials: C
authors.lastname: Tran
authors.forename: Francis Y
authors.initials: FY
authors.lastname: Lee
authors.forename: Ping
authors.initials: P
authors.lastname: Chen
authors.forename: Derek
authors.initials: D
authors.lastname: Norris
authors.forename: Charles L
authors.initials: CL
authors.lastname: Sawyers
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D001549:Benzamides; D001665:Binding Sites; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D017321:Clinical Trials, Phase I as Topic; D000069439:Dasatinib; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D051379:Mice; D016513:Mice, SCID; D009154:Mutation; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D011487:Protein Conformation; D011743:Pyrimidines / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D013844:Thiazoles / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; D010879:Piperazines; D011743:Pyrimidines; D013844:Thiazoles; C406060:abl-bcr fusion protein, human; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D000069439:Dasatinib