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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.

Authors: Chan, WW  Wise, SC  Kaufman, MD  Ahn, YM  Ensinger, CL  Haack, T  Hood, MM  Jones, J  Lord, JW  Lu, WP  Miller, D  Patt, WC  Smith, BD  Petillo, PA  Rutkoski, TJ  Telikepalli, H  Vogeti, L  Yao, T  Chun, L  Clark, R  Evangelista, P  Gavrilescu, LC  Lazarides, K  Zaleskas, VM  Stewart, LJ  Van Etten, RA  Flynn, DL 
Citation: Chan WW, etal., Cancer Cell. 2011 Apr 12;19(4):556-68. doi: 10.1016/j.ccr.2011.03.003.
Pubmed: (View Article at PubMed) PMID:21481795
DOI: Full-text: DOI:10.1016/j.ccr.2011.03.003

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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CRRD Object Information
CRRD ID: 11038814
Created: 2016-02-26
Species: All species
Last Modified: 2016-02-26
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.