MYELOID NEOPLASIA Discovery of a small-molecule type II inhibitor of wild-type and gatekeeper mutants of BCR-ABL, PDGFR , Kit, and Src kinases: novel type II inhibitor of gatekeeper mutants
نویسندگان
چکیده
*Ellen Weisberg,1 *Hwan Geun Choi,2 *Arghya Ray,1 Rosemary Barrett,1 Jianming Zhang,2 Taebo Sim,2 Wenjun Zhou,2 Markus Seeliger,3 Michael Cameron,4 Mohammed Azam,5 Jonathan A. Fletcher,6 Maria Debiec-Rychter,7 Mark Mayeda,6 Daisy Moreno,8 Andrew L. Kung,9 Pasi Antero Janne,1 Roya Khosravi-Far,10 Junia V. Melo,11 Paul W. Manley,12 Sophia Adamia,1 Catherine Wu,1 Nathanael Gray,2 and James D. Griffin1
منابع مشابه
A type-II kinase inhibitor capable of inhibiting the T315I "gatekeeper" mutant of Bcr-Abl.
The second generation of Bcr-Abl inhibitors nilotinib, dasatinib, and bosutinib developed to override imatinib resistance are not active against the T315I "gatekeeper" mutation. Here we describe a type-II T315I inhibitor 2 (GNF-7), based upon a 3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one scaffold which is capable of potently inhibiting wild-type and T315I Bcr-Abl as well as other clinically r...
متن کاملPhosphorylation of the ATP-binding loop directs oncogenicity of drug-resistant BCR-ABL mutants.
The success of targeting kinases in cancer with small molecule inhibitors has been tempered by the emergence of drug-resistant kinase domain mutations. In patients with chronic myeloid leukemia treated with ABL inhibitors, BCR-ABL kinase domain mutations are the principal mechanism of relapse. Certain mutations are occasionally detected before treatment, suggesting increased fitness relative to...
متن کاملSimultaneous targeting of Aurora kinases and Bcr-Abl kinase by the small molecule inhibitor PHA-739358 is effective against imatinib-resistant BCR-ABL mutations including T315I.
The emergence of resistance to imatinib (IM) mediated by mutations in the BCR-ABL domain has become a major challenge in the treatment of chronic myeloid leukemia (CML). Here, we report on studies performed with a novel small molecule inhibitor, PHA-739358, which selectively targets Bcr-Abl and Aurora kinases A to C. PHA-739358 exhibits strong antiproliferative and proapoptotic activity against...
متن کاملInhibitors of the Abl kinase directed at either the ATP- or myristate-binding site.
The ATP-competitive inhibitors dasatinib and nilotinib, which bind to catalytically different conformations of the Abl kinase domain, have recently been approved for the treatment of imatinib-resistant CML. These two new drugs, albeit very efficient against most of the imatinib-resistant mutants of Bcr-Abl, fail to effectively suppress the Bcr-Abl activity of the T315I (or gatekeeper) mutation....
متن کاملCombined Abl inhibitor therapy for minimizing drug resistance in chronic myeloid leukemia: Src/Abl inhibitors are compatible with imatinib.
PURPOSE Chronic myeloid leukemia (CML) is effectively treated with imatinib. However, reactivation of Bcr-Abl via kinase domain mutations that reduce sensitivity to imatinib can cause relapse. As combination therapy is frequently used to prevent emergence of resistance, the combination of imatinib with an inhibitor of imatinib-resistant Bcr-Abl mutants (e.g., Src/Abl inhibitors AP23848 and BMS-...
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