2. Academic Validation
  3. Optimization of PDE3A Modulators for SLFN12-Dependent Cancer Cell Killing

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.
Timothy A Lewis 1,  Luc de Waal 1 2,  Xiaoyun Wu 1 2,  Willmen Youngsaye 1,  Antje Wengner 3,  Charlotte Kopitz 3,  Martin Lange 3,  Stefan Gradl 3,  Manuel Ellermann 3,  Philip Lienau 3,  Stuart L Schreiber 1,  Heidi Greulich 1 2,  Matthew Meyerson 1 2
Affiliations

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.
PMID: 31749907 DOI: 10.1021/acsmedchemlett.9b00360
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.

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