Cancer cell, 2011-04, Vol.19 (4), p.556-568
- 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.
2011
Volltextzugriff (PDF)
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- Autor(en) / Beteiligte
- 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.
- Titel
- Conformational Control Inhibition of the BCR-ABL1 Tyrosine Kinase, Including the Gatekeeper T315I Mutant, by the Switch-Control Inhibitor DCC-2036
- Ist Teil von
- Cancer cell, 2011-04, Vol.19 (4), p.556-568
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2011
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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. ► Switch-control inhibitors exploit mechanisms of kinase conformational shifts ► Switch-control inhibitor DCC-2036 potently inhibits BCR-ABL1 gatekeeper mutant T315I ► DCC-2036 has efficacy in a mouse model of T315I-induced CML and against cells of patients with CML ► DCC-2036 may be an option for therapy of patients with CML for whom conventional TKIs fail
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1535-6108eISSN: 1878-3686DOI: 10.1016/j.ccr.2011.03.003Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3077923
- Format
- –
- Schlagworte
- 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