Optimization of PDE3A Modulators for SLFN12-Dependent Cancer Cell Killing

Timothy A Lewis; Luc de Waal; Xiaoyun Wu; Willmen Youngsaye; Antje Wengner; Charlotte Kopitz; Martin Lange; Stefan Gradl; Manuel Ellermann; Philip Lienau; Stuart L Schreiber; Heidi Greulich; Matthew Meyerson

doi:10.1021/acsmedchemlett.9b00360

Optimization of PDE3A Modulators for SLFN12-Dependent Cancer Cell Killing

ACS Med Chem Lett. 2019 Oct 18;10(11):1537-1542. doi: 10.1021/acsmedchemlett.9b00360. eCollection 2019 Nov 14.

Authors

Timothy A Lewis¹, Luc de Waal^{1

2}, Xiaoyun Wu^{1

2}, Willmen Youngsaye¹, Antje Wengner³, Charlotte Kopitz³, Martin Lange³, Stefan Gradl³, Manuel Ellermann³, Philip Lienau³, Stuart L Schreiber¹, Heidi Greulich^{1

2}, Matthew Meyerson^{1

2}

Affiliations

¹ Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States.
² Dana-Farber Cancer Institute, Boston, Massachusetts 01255, United States.
³ Bayer AG, Berlin, Germany.

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.