Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl.
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.
Weisberg
Ellen
E
Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Manley
Paul W
PW
Breitenstein
Werner
W
Brüggen
Josef
J
Cowan-Jacob
Sandra W
SW
Ray
Arghya
A
Huntly
Brian
B
Fabbro
Doriano
D
Fendrich
Gabriele
G
Hall-Meyers
Elizabeth
E
Kung
Andrew L
AL
Mestan
Jürgen
J
Daley
George Q
GQ
Callahan
Linda
L
Catley
Laurie
L
Cavazza
Cara
C
Azam
Mohammad
M
Mohammed
Azam
A
Neuberg
Donna
D
Wright
Renee D
RD
Gilliland
D Gary
DG
Griffin
James D
JD
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
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; C498826:nilotinib