Author/Authors :
Weisberg، نويسنده , , Ellen and Manley، نويسنده , , Paul W. and Breitenstein، نويسنده , , Werner and Brüggen، نويسنده , , Josef and Cowan-Jacob، نويسنده , , Sandra W. and Ray، نويسنده , , Arghya and Huntly، نويسنده , , Brian and Fabbro، نويسنده , , Doriano and Fendrich، نويسنده , , Gabriele and Hall-Meyers، نويسنده , , Elizabeth and Kung، نويسنده , , Andrew L. and Mestan، نويسنده , , Jürgen and Daley، نويسنده , , George Q. and Callahan، نويسنده , , Linda and Catley، نويسنده , , Laurie and Cavazza، نويسنده , , Cara and Mohammed، نويسنده , , Azam and Neuberg، نويسنده , , Donna J. Wright، نويسنده , , Renee D. and Gilliland، نويسنده , , D. Gary and Griffin، نويسنده , , James D.، نويسنده ,
Abstract :
Summary
r-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.
