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

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.
Wayne W Chan 1,  Scott C Wise,  Michael D Kaufman,  Yu Mi Ahn,  Carol L Ensinger,  Torsten Haack,  Molly M Hood,  Jennifer Jones,  John W Lord,  Wei Ping Lu,  David Miller,  William C Patt,  Bryan D Smith,  Peter A Petillo,  Thomas J Rutkoski,  Hanumaiah Telikepalli,  Lakshminarayana Vogeti,  Tony Yao,  Lawrence Chun,  Robin Clark,  Peter Evangelista,  L Cristina Gavrilescu,  Katherine Lazarides,  Virginia M Zaleskas,  Lance J Stewart,  Richard A Van Etten,  Daniel L Flynn
Affiliations

Affiliation

  • 1 Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111, USA.
PMID: 21481795 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.

Figures
Products