Abstract C136: Identification of selective cancer cytotoxic modulators of phosphodiesterase 3a by predictive chemogenomics

Abstract

Abstract High 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 identify 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 demonstrate 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 sensitivity to DNMDP. Our results implicate PDE3A modulators as candidate cancer therapeutic agents and demonstrate the power of predictive chemogenomics in small-molecule discovery. Citation Format: Lucian de Waal, Timothy A. Lewis, Matthew G. Rees, Aviad Tsherniak, Xiaoyun Wu, Peter S. Choi, Lara Gechijian, Christina Hartigan, Patrick W. Faloon, Mark J. Hickey, Nicola Tolliday, Steven A. Carr, Paul A. Clemons, Benito Munoz, Bridget K. Wagner, Alykhan F. Shamji, Angela N. Koehler, Monica Schenone, Alex B. Burgin, Stuart L. Schreiber, Heidi Greulich, Matthew Meyerson. Identification of selective cancer cytotoxic modulators of phosphodiesterase 3a by predictive chemogenomics. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C136.