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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This work was supported in part by the US National Cancer Institute (NCI) Grant (grant number 1R35CA197568, awarded to M.M.), the American Cancer Society Research Professorship (awarded to M.M.), the Doctors Cancer Foundation (awarded to H.G.), the Friends of Dana-Farber Cancer Institute (awarded to H.G.), and the US National Institutes of Health's Molecular Libraries Program Center Network (MLPCN) (grant number 3U54HG005032-05S1, awarded to H.G., M.M. and S.L.S.). The cancer cell-line profiling studies were supported in part by the NCI's Cancer Target Discovery and Development (CTD2) Network (grant number U01CA176152, awarded to S.L.S.). We thank A. Bhatt, H. Gannon, J. Jung, T. Sharifnia and all members of the Meyerson laboratory for their advice and helpful discussions. S.L.S. is an Investigator of the Howard Hughes Medical Institute.
L.d.W., T.A.L., X.W., P.A.C., S.L.S., H.G. and M.M. receive research support from Bayer. M.M. is a founder, consultant and equity holder in Foundation Medicine. L.d.W., T.A.L., L.G., B.M., H.G. and M.M. are inventors on patent WO 2014/164704 A2, covering the chemical space around DNMDP and some of the analogs described in the supplementary information.
Supplementary Results, Supplementary Figures 1–11, Supplementary Tables 1–6 and Supplementary Note. (PDF 2030 kb)
Screening data of 1924 compounds in A549 and NCI-H1734 (XLSX 293 kb)
Sensitivity data of 766 cancer cell lines treated with DNMDP (XLSX 70 kb)
Results from competition screen using 1600 bioactive compounds to rescue DNMDP cytotoxicity in the HeLa cell line. (XLSX 135 kb)
Results from PDE3A immunoprecipitation followed by iTRAQ/MS in the presence of blocking peptide, DMSO, DNMDP and trequinsin. (XLSX 1345 kb)
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de Waal, L., Lewis, T., Rees, M. et al. Identification of cancer-cytotoxic modulators of PDE3A by predictive chemogenomics. Nat Chem Biol 12, 102–108 (2016). https://doi.org/10.1038/nchembio.1984
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