Optimization of PDE3A Modulators for SLFN12-Dependent Cancer Cell Killing

Abstract

6-(4-(Diethylamino)-3-nitrophenyl)-5-methyl-4,5-dihydropyridazin-3(2<i>H</i>)-one, or <b>DNMDP</b>, potently and selectively inhibits phosphodiesterases 3A and 3B (PDE3A and PDE3B) and kills cancer cells by inducing PDE3A/B interactions with SFLN12. The structure-activity relationship (SAR) of <b>DNMDP</b> analogs was evaluated using a phenotypic viability assay, resulting in several compounds with suitable pharmacokinetic properties for <i>in vivo</i> analysis. One of these compounds, <b>BRD9500</b>, was active in an SK-MEL-3 xenograft model of cancer.