Author/Authors :
Chan، نويسنده , , Wayne W. and Wise، نويسنده , , Scott C. and Kaufman، نويسنده , , Michael D. and Ahn، نويسنده , , Yu Mi and Ensinger، نويسنده , , Carol L. and Haack، نويسنده , , Torsten and Hood، نويسنده , , Molly M. and Jones، نويسنده , , Jennifer and Lord، نويسنده , , John W. and Lu، نويسنده , , Wei Ping and Miller، نويسنده , , David and Patt، نويسنده , , William C. and Smith، نويسنده , , Bryan D. and Petillo، نويسنده , , Peter A. and Rutkoski، نويسنده , , Thomas J. and Telikepalli، نويسنده , , Hanumaiah and Vogeti، نويسنده , , Lakshminarayana and Yao، نويسنده , , Tony and Chun، نويسنده , , Lawrence and Clark، نويسنده , , Robin and Evangelista، نويسنده , , Peter and Gavrilescu، نويسنده , , L. Cristina and Lazarides، نويسنده , , Katherine and Zaleskas، نويسنده , , Virginia M. and Stewart، نويسنده , , Lance J. and Van Etten، نويسنده , , Richard A. and Flynn، نويسنده , , Daniel L.، نويسنده ,
Abstract :
Summary
ed resistance to ABL1 tyrosine kinase inhibitors (TKIs) through ABL1 kinase domain mutations, particularly the gatekeeper mutant T315I, is a significant problem for patients with chronic myeloid leukemia (CML). Using structure-based drug design, we developed compounds that bind to residues (Arg386/Glu282) ABL1 uses to switch between inactive and active conformations. The lead “switch-control” inhibitor, DCC-2036, potently inhibits both unphosphorylated and phosphorylated ABL1 by inducing a type II inactive conformation, and retains efficacy against the majority of clinically relevant CML-resistance mutants, including T315I. DCC-2036 inhibits BCR-ABL1T315I-expressing cell lines, prolongs survival in mouse models of T315I mutant CML and B-lymphoblastic leukemia, and inhibits primary patient leukemia cells expressing T315I in vitro and in vivo, supporting its clinical development in TKI-resistant Ph+ leukemia.
