The Meyerson lab recently discovered a small molecule compound, DNMDP (6-(4-(diethylamino)-3-nitrophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one) that selectively kills cancer cell llnes at nM potency (de Waal et al, 2016). Unlike typical targeted therapies that leverage dependencies in cancer cells created by genomic alterations, DNMDP induces cancer cell death by a gain-of-function mechanism involving the formation of a complex between phosphodiesterase 3A (PDE3A) and schlafen family member 12 (SLFN12). To probe the mechanism of action of DNMDP, Xiaoyun et al. studied the genomic determinants of cancer cell response to DNMDP, finding a linear correlation between DNMDP sensitivity and PDE3A protein levels, and a requirement for expression of SLFN12 and the aryl hydrocarbon receptor-interacting protein, AIP. They further demonstrated that the PDE3A catalytic domain is necessary and sufficient for mediating sensitivity to DNMDP, and that PDE3B can substitute for PDE3A. In the absence of AIP, there is no PDE3A-SLFN12 complex formation and cells no longer respond to DNMDP-induced cancer cell killing. This study provides new insight into how DNMDP, through the PDE3A-SLFN12 complex, mediates cell death.