One approach to identifying new anticancer agents is phenotypic screening. To discover small molecules with cytotoxic activity, a phenotypic screen was in two lung adenocarcinoma cell lines, A549 and NCI-H1734. This screen resulted in the identification of DNMDP as a selective cancer-cytotoxic small molecule with a low-nanomolar IC50 over many tested cell lines. The activity of this compound was further tested against 766 additional cancer cell lines, and through chemogenomic analysis as part of the Cancer Cell Line Encyclopedia (CCLE), a strong correlation between DNMDP sensitivity and the expression of the gene encoding phosphodiesterase 3A (PDE3A) was made. PDE3A is a member of the cyclic nucleotide phosphodiesterase family of enzymes which catalyze the hydrolysis of cAMP and cGMP and are important in many physiological processes. The binding of DNMDP to PDE3A promotes an interaction between PDE3A and Schlafen 12 (SLFN12), and it is postulated that this interaction is responsible for the small molecule’s anticancer activity. Nat. Chem. Biol., 2016, 12(2), 102-108.