title: Activity of the Bcr-Abl kinase inhibitor PD180970 against clinically relevant Bcr-Abl isoforms that cause resistance to imatinib mesylate (Gleevec, STI571).
abstract: Imatinib mesylate, a selective inhibitor of the Abl tyrosine kinase, is effective as a single-agent therapy for chronic myelogenous leukemia. However, resistance has been reported, particularly in patients with advanced-stage disease. Mutations within the Abl kinase domain are a major cause of resistance, demonstrating that Bcr-Abl remains a critical drug target. Recently, a novel pyrido[2,3-d]pyrimidine derivative, PD180970, has been shown to potently inhibit Bcr-Abl and induce apoptosis in Bcr-Abl-expressing leukemic cells. We analyzed the inhibitory activity of PD180970 against Abl kinase domain mutations and cells expressing clinically relevant mutations. Our data indicate that PD180970 is active against several Bcr-Abl mutations that are resistant to imatinib and support the notion that developing additional Abl kinase inhibitors would be useful as a treatment strategy for chronic myelogenous leukemia.
authors.affiliation: Oregon Health and Sciences University Cancer Institute, Division of Hematology and Medical Oncology, Portland, Oregon 97239, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: La Rosée
authors.forename: Amie S
authors.initials: AS
authors.lastname: Corbin
authors.forename: Eric P
authors.initials: EP
authors.lastname: Stoffregen
authors.forename: Michael W
authors.initials: MW
authors.lastname: Deininger
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Druker
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides; D002460:Cell Line; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016044:Fusion Proteins, bcr-abl; D006412:Hematopoietic Stem Cells / Q000201:enzymology / Q000502:physiology; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D051379:Mice; D016297:Mutagenesis, Site-Directed; D010879:Piperazines / Q000494:pharmacology*; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D011728:Pyridones / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; D010879:Piperazines; D020033:Protein Isoforms; D011728:Pyridones; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; C410732:PD 180970