title: Allosteric inhibitors of Bcr-abl-dependent cell proliferation.
abstract: Chronic myelogenous leukemia (CML) is a myeloproliferative disorder characterized at the molecular level by the expression of Bcr-abl, a 210-kDa fusion protein with deregulated tyrosine kinase activity. Encouraged by the clinical validation of Bcr-abl as the target for the treatment of CML by imatinib, we sought to identify pharmacological agents that could target this kinase by a distinct mechanism. We report the discovery of a new class of Bcr-abl inhibitors using an unbiased differential cytotoxicity screen of a combinatorial kinase-directed heterocycle library. Compounds in this class (exemplified by GNF-2) show exclusive antiproliferative activity toward Bcr-abl-transformed cells, with potencies similar to imatinib, while showing no inhibition of the kinase activity of full-length or catalytic domain of c-abl. We propose that this new class of compounds inhibits Bcr-abl kinase activity through an allosteric non-ATP competitive mechanism.
authors.affiliation: Biological Chemistry Department, Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Adrián
authors.forename: Qiang
authors.initials: Q
authors.lastname: Ding
authors.forename: Taebo
authors.initials: T
authors.lastname: Sim
authors.forename: Anastasia
authors.initials: A
authors.lastname: Velentza
authors.forename: Christine
authors.initials: C
authors.lastname: Sloan
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.forename: Guobao
authors.initials: G
authors.lastname: Zhang
authors.forename: Wooyoung
authors.initials: W
authors.lastname: Hur
authors.forename: Sheng
authors.initials: S
authors.lastname: Ding
authors.forename: Paul
authors.initials: P
authors.lastname: Manley
authors.forename: Jürgen
authors.initials: J
authors.lastname: Mestan
authors.forename: Doriano
authors.initials: D
authors.lastname: Fabbro
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D001549:Benzamides; D002460:Cell Line; D002461:Cell Line, Transformed; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy; D051379:Mice; D010879:Piperazines / Q000494:pharmacology*; D011485:Protein Binding; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; C508526:GNF-2 compound; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl