title: Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl.
abstract: The Bcr-Abl tyrosine kinase oncogene causes chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). We describe a novel selective inhibitor of Bcr-Abl, AMN107 (IC50 <30 nM), which is significantly more potent than imatinib, and active against a number of imatinib-resistant Bcr-Abl mutants. Crystallographic analysis of Abl-AMN107 complexes provides a structural explanation for the differential activity of AMN107 and imatinib against imatinib-resistant Bcr-Abl. Consistent with its in vitro and pharmacokinetic profile, AMN107 prolonged survival of mice injected with Bcr-Abl-transformed hematopoietic cell lines or primary marrow cells, and prolonged survival in imatinib-resistant CML mouse models. AMN107 is a promising new inhibitor for the therapy of CML and Ph+ ALL.
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors.forename: Ellen
authors.initials: E
authors.lastname: Weisberg
authors.forename: Paul W
authors.initials: PW
authors.lastname: Manley
authors.forename: Werner
authors.initials: W
authors.lastname: Breitenstein
authors.forename: Josef
authors.initials: J
authors.lastname: Brüggen
authors.forename: Sandra W
authors.initials: SW
authors.lastname: Cowan-Jacob
authors.forename: Arghya
authors.initials: A
authors.lastname: Ray
authors.forename: Brian
authors.initials: B
authors.lastname: Huntly
authors.forename: Doriano
authors.initials: D
authors.lastname: Fabbro
authors.forename: Gabriele
authors.initials: G
authors.lastname: Fendrich
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hall-Meyers
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Kung
authors.forename: Jürgen
authors.initials: J
authors.lastname: Mestan
authors.forename: George Q
authors.initials: GQ
authors.lastname: Daley
authors.forename: Linda
authors.initials: L
authors.lastname: Callahan
authors.forename: Laurie
authors.initials: L
authors.lastname: Catley
authors.forename: Cara
authors.initials: C
authors.lastname: Cavazza
authors.forename: Mohammad
authors.initials: M
authors.lastname: Azam
authors.forename: Azam
authors.initials: A
authors.lastname: Mohammed
authors.forename: Donna
authors.initials: D
authors.lastname: Neuberg
authors.forename: Renee D
authors.initials: RD
authors.lastname: Wright
authors.forename: D Gary
authors.initials: DG
authors.lastname: Gilliland
authors.forename: James D
authors.initials: JD
authors.lastname: Griffin
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides; D001854:Bone Marrow Cells / Q000166:cytology; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000166:cytology; D000068877:Imatinib Mesylate; D020128:Inhibitory Concentration 50; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D051379:Mice; D008954:Models, Biological; D008956:Models, Chemical; D009154:Mutation; D009174:Mycoplasma / Q000378:metabolism; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology*; D012190:Retroviridae / Q000235:genetics; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; C498826:nilotinib