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Identification of cancer-cytotoxic modulators of PDE3A by predictive chemogenomics.
de Waal, Luc; Lewis, Timothy A; Rees, Matthew G; Tsherniak, Aviad; Wu, Xiaoyun; Choi, Peter S; Gechijian, Lara; Hartigan, Christina; Faloon, Patrick W; Hickey, Mark J; Tolliday, Nicola; Carr, Steven A; Clemons, Paul A; Munoz, Benito; Wagner, Bridget K; Shamji, Alykhan F; Koehler, Angela N; Schenone, Monica; Burgin, Alex B; Schreiber, Stuart L; Greulich, Heidi; Meyerson, Matthew.
  • de Waal L; The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
  • Lewis TA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
  • Rees MG; The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
  • Tsherniak A; The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
  • Wu X; The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
  • Choi PS; The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
  • Gechijian L; The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
  • Hartigan C; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
  • Faloon PW; The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
  • Hickey MJ; The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
  • Tolliday N; The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
  • Carr SA; The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
  • Clemons PA; The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
  • Munoz B; The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
  • Wagner BK; The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
  • Shamji AF; The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
  • Koehler AN; The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
  • Schenone M; The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
  • Burgin AB; The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
  • Schreiber SL; Koch Institute for Integrative Cancer Research at MIT, Cambridge, Massachusetts, USA.
  • Greulich H; The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
  • Meyerson M; The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
Nat Chem Biol ; 12(2): 102-8, 2016 Feb.
Article en En | MEDLINE | ID: mdl-26656089
ABSTRACT
High cancer death rates indicate the need for new anticancer therapeutic agents. Approaches to discovering new cancer drugs include target-based drug discovery and phenotypic screening. Here, we identified phosphodiesterase 3A modulators as cell-selective cancer cytotoxic compounds through phenotypic compound library screening and target deconvolution by predictive chemogenomics. We found that sensitivity to 6-(4-(diethylamino)-3-nitrophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one, or DNMDP, across 766 cancer cell lines correlates with expression of the gene PDE3A, encoding phosphodiesterase 3A. Like DNMDP, a subset of known PDE3A inhibitors kill selected cancer cells, whereas others do not. Furthermore, PDE3A depletion leads to DNMDP resistance. We demonstrated that DNMDP binding to PDE3A promotes an interaction between PDE3A and Schlafen 12 (SLFN12), suggestive of a neomorphic activity. Coexpression of SLFN12 with PDE3A correlates with DNMDP sensitivity, whereas depletion of SLFN12 results in decreased DNMDP sensitivity. Our results implicate PDE3A modulators as candidate cancer therapeutic agents and demonstrate the power of predictive chemogenomics in small-molecule discovery.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Piridazinas / Citotoxinas / Fosfodiesterasas de Nucleótidos Cíclicos Tipo 3 / Neoplasias Tipo de estudio: Diagnostic_studies / Prognostic_studies / Risk_factors_studies Límite: Humans Idioma: En Año: 2016 Tipo del documento: Article
Texto completo
Imprimir
XML
PubMed Links
Search on Google

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Piridazinas / Citotoxinas / Fosfodiesterasas de Nucleótidos Cíclicos Tipo 3 / Neoplasias Tipo de estudio: Diagnostic_studies / Prognostic_studies / Risk_factors_studies Límite: Humans Idioma: En Año: 2016 Tipo del documento: Article