학술논문
Conformational control inhibition of the BCR-ABL1 tyrosine kinase, including the gatekeeper T315I mutant, by the switch-control inhibitor DCC-2036.
Document Type
article
Author
Chan, Wayne W; Wise, Scott C; Kaufman, Michael D; Ahn, Yu Mi; Ensinger, Carol L; Haack, Torsten; Hood, Molly M; Jones, Jennifer; Lord, John W; Lu, Wei Ping; Miller, David; Patt, William C; Smith, Bryan D; Petillo, Peter A; Rutkoski, Thomas J; Telikepalli, Hanumaiah; Vogeti, Lakshminarayana; Yao, Tony; Chun, Lawrence; Clark, Robin; Evangelista, Peter; Gavrilescu, L Cristina; Lazarides, Katherine; Zaleskas, Virginia M; Stewart, Lance J; Van Etten, Richard A; Flynn, Daniel L
Source
Cancer cell. 19(4)
Subject
Language
Abstract
Acquired 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-ABL1(T315I)-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.