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dc.contributor.authorde Waal, Lucen_US
dc.contributor.authorLewis, Timothy A.en_US
dc.contributor.authorRees, Matthew G.en_US
dc.contributor.authorTsherniak, Aviaden_US
dc.contributor.authorWu, Xiaoyunen_US
dc.contributor.authorChoi, Peter S.en_US
dc.contributor.authorGechijian, Laraen_US
dc.contributor.authorHartigan, Christinaen_US
dc.contributor.authorFaloon, Patrick W.en_US
dc.contributor.authorHickey, Mark J.en_US
dc.contributor.authorTolliday, Nicolaen_US
dc.contributor.authorCarr, Steven A.en_US
dc.contributor.authorClemons, Paul A.en_US
dc.contributor.authorMunoz, Benitoen_US
dc.contributor.authorWagner, Bridget K.en_US
dc.contributor.authorShamji, Alykhan F.en_US
dc.contributor.authorKoehler, Angela N.en_US
dc.contributor.authorSchenone, Monicaen_US
dc.contributor.authorBurgin, Alex B.en_US
dc.contributor.authorSchreiber, Stuart L.en_US
dc.contributor.authorGreulich, Heidien_US
dc.contributor.authorMeyerson, Matthewen_US
dc.date.accessioned2016-07-14T19:17:02Z
dc.date.issued2015en_US
dc.identifier.citationde Waal, L., T. A. Lewis, M. G. Rees, A. Tsherniak, X. Wu, P. S. Choi, L. Gechijian, et al. 2015. “Identification of cancer cytotoxic modulators of PDE3A by predictive chemogenomics.” Nature chemical biology 12 (2): 102-108. doi:10.1038/nchembio.1984. http://dx.doi.org/10.1038/nchembio.1984.en
dc.identifier.issn1552-4450en
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:27662215
dc.description.abstractHigh cancer death rates indicate the need for new anti-cancer therapeutic agents. Approaches to discover new cancer drugs include target-based drug discovery and phenotypic screening. Here, we identified phosphodiesterase 3A modulators as cell-selective cancer cytotoxic compounds by 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 phosphodiesterase 3A gene, PDE3A. Like DNMDP, a subset of known PDE3A inhibitors kill selected cancer cells while 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), suggesting a neomorphic activity. Co-expression of SLFN12 with PDE3A correlates with DNMDP sensitivity, while 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.en
dc.language.isoen_USen
dc.relation.isversionofdoi:10.1038/nchembio.1984en
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC4718766/pdf/en
dash.licenseLAAen_US
dc.titleIdentification of cancer cytotoxic modulators of PDE3A by predictive chemogenomicsen
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden
dc.relation.journalNature chemical biologyen
dash.depositing.authorChoi, Peter S.en_US
dc.date.available2016-07-14T19:17:02Z
dc.identifier.doi10.1038/nchembio.1984*
dash.authorsorderedfalse
dash.contributor.affiliatedShamji, Alykhan
dash.contributor.affiliatedGreulich, Heidi
dash.contributor.affiliatedChoi, Peter
dash.contributor.affiliatedSchreiber, Stuart
dash.contributor.affiliatedMeyerson, Matthew
dc.identifier.orcid0000-0002-9133-8108


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