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

Cancer Cell. 2011 Apr 12;19(4):556-68. doi: 10.1016/j.ccr.2011.03.003.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Drug Design
  • Fusion Proteins, bcr-abl / antagonists & inhibitors*
  • Fusion Proteins, bcr-abl / chemistry
  • Humans
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mutation*
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
  • Protein Conformation
  • Protein Kinase Inhibitors / pharmacology*
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / chemistry

Substances

  • Protein Kinase Inhibitors
  • Protein-Tyrosine Kinases
  • Fusion Proteins, bcr-abl

Associated data

  • PDB/3QRI
  • PDB/3QRJ
  • PDB/3QRK