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An inhibitor of KDM5 demethylases reduces survival of drug-tolerant cancer cells.
Vinogradova, Maia; Gehling, Victor S; Gustafson, Amy; Arora, Shilpi; Tindell, Charles A; Wilson, Catherine; Williamson, Kaylyn E; Guler, Gulfem D; Gangurde, Pranoti; Manieri, Wanda; Busby, Jennifer; Flynn, E Megan; Lan, Fei; Kim, Hyo-Jin; Odate, Shobu; Cochran, Andrea G; Liu, Yichin; Wongchenko, Matthew; Yang, Yibin; Cheung, Tommy K; Maile, Tobias M; Lau, Ted; Costa, Michael; Hegde, Ganapati V; Jackson, Erica; Pitti, Robert; Arnott, David; Bailey, Christopher; Bellon, Steve; Cummings, Richard T; Albrecht, Brian K; Harmange, Jean-Christophe; Kiefer, James R; Trojer, Patrick; Classon, Marie.
Affiliation
  • Vinogradova M; Genentech Inc., South San Francisco, California, USA.
  • Gehling VS; Constellation Pharmaceuticals, Cambridge, Massachusetts, USA.
  • Gustafson A; Genentech Inc., South San Francisco, California, USA.
  • Arora S; Constellation Pharmaceuticals, Cambridge, Massachusetts, USA.
  • Tindell CA; Genentech Inc., South San Francisco, California, USA.
  • Wilson C; Genentech Inc., South San Francisco, California, USA.
  • Williamson KE; Constellation Pharmaceuticals, Cambridge, Massachusetts, USA.
  • Guler GD; Genentech Inc., South San Francisco, California, USA.
  • Gangurde P; Constellation Pharmaceuticals, Cambridge, Massachusetts, USA.
  • Manieri W; Constellation Pharmaceuticals, Cambridge, Massachusetts, USA.
  • Busby J; Constellation Pharmaceuticals, Cambridge, Massachusetts, USA.
  • Flynn EM; Genentech Inc., South San Francisco, California, USA.
  • Lan F; Constellation Pharmaceuticals, Cambridge, Massachusetts, USA.
  • Kim HJ; Genentech Inc., South San Francisco, California, USA.
  • Odate S; Constellation Pharmaceuticals, Cambridge, Massachusetts, USA.
  • Cochran AG; Genentech Inc., South San Francisco, California, USA.
  • Liu Y; Genentech Inc., South San Francisco, California, USA.
  • Wongchenko M; Genentech Inc., South San Francisco, California, USA.
  • Yang Y; Genentech Inc., South San Francisco, California, USA.
  • Cheung TK; Genentech Inc., South San Francisco, California, USA.
  • Maile TM; Genentech Inc., South San Francisco, California, USA.
  • Lau T; Genentech Inc., South San Francisco, California, USA.
  • Costa M; Genentech Inc., South San Francisco, California, USA.
  • Hegde GV; Genentech Inc., South San Francisco, California, USA.
  • Jackson E; Genentech Inc., South San Francisco, California, USA.
  • Pitti R; Genentech Inc., South San Francisco, California, USA.
  • Arnott D; Genentech Inc., South San Francisco, California, USA.
  • Bailey C; Constellation Pharmaceuticals, Cambridge, Massachusetts, USA.
  • Bellon S; Constellation Pharmaceuticals, Cambridge, Massachusetts, USA.
  • Cummings RT; Constellation Pharmaceuticals, Cambridge, Massachusetts, USA.
  • Albrecht BK; Constellation Pharmaceuticals, Cambridge, Massachusetts, USA.
  • Harmange JC; Constellation Pharmaceuticals, Cambridge, Massachusetts, USA.
  • Kiefer JR; Genentech Inc., South San Francisco, California, USA.
  • Trojer P; Constellation Pharmaceuticals, Cambridge, Massachusetts, USA.
  • Classon M; Genentech Inc., South San Francisco, California, USA.
Nat Chem Biol ; 12(7): 531-8, 2016 07.
Article in En | MEDLINE | ID: mdl-27214401
ABSTRACT
The KDM5 family of histone demethylases catalyzes the demethylation of histone H3 on lysine 4 (H3K4) and is required for the survival of drug-tolerant persister cancer cells (DTPs). Here we report the discovery and characterization of the specific KDM5 inhibitor CPI-455. The crystal structure of KDM5A revealed the mechanism of inhibition of CPI-455 as well as the topological arrangements of protein domains that influence substrate binding. CPI-455 mediated KDM5 inhibition, elevated global levels of H3K4 trimethylation (H3K4me3) and decreased the number of DTPs in multiple cancer cell line models treated with standard chemotherapy or targeted agents. These findings show that pretreatment of cancer cells with a KDM5-specific inhibitor results in the ablation of a subpopulation of cancer cells that can serve as the founders for therapeutic relapse.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Drug Resistance, Neoplasm / Enzyme Inhibitors / Retinoblastoma-Binding Protein 2 / Neoplasms / Antineoplastic Agents Type of study: Prognostic_studies Limits: Humans Language: En Journal: Nat Chem Biol Journal subject: BIOLOGIA / QUIMICA Year: 2016 Document type: Article Affiliation country: Estados Unidos
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Drug Resistance, Neoplasm / Enzyme Inhibitors / Retinoblastoma-Binding Protein 2 / Neoplasms / Antineoplastic Agents Type of study: Prognostic_studies Limits: Humans Language: En Journal: Nat Chem Biol Journal subject: BIOLOGIA / QUIMICA Year: 2016 Document type: Article Affiliation country: Estados Unidos