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Conformational control inhibition of the BCR-ABL1 tyrosine kinase, including the gatekeeper T315I mutant, by the switch-control inhibitor DCC-2036.

  • Author(s): 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
  • et al.
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.

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