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

WW Chan, SC Wise, MD Kaufman, YM Ahn… - Cancer cell, 2011 - cell.com
WW Chan, SC Wise, MD Kaufman, YM Ahn, CL Ensinger, T Haack, MM Hood, J Jones
Cancer cell, 2011cell.com
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 …
Summary
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-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.
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