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Published on: January 7, 2019
Optimization of PDE3A Modulators for SLFN12-Dependent Cancer Cell Killing
Timothy A Lewis1, Luc de Waal1,2, Xiaoyun Wu1,2
1Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States.
Abstract:
6-(4-(Diethylamino)-3-nitrophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one, or DNMDP, 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 DNMDP analogs was evaluated using a phenotypic viability assay, resulting in several compounds with suitable pharmacokinetic properties for in vivo analysis. One of these compounds, BRD9500, was active in an SK-MEL-3 xenograft model of cancer.
