Optimization of PDE3A Modulators for SLFN12-Dependent Cancer Cell Killing.

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

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

Afiliação

Lewis TA; Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States.
de Waal L; Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States.
Wu X; Dana-Farber Cancer Institute, Boston, Massachusetts 01255, United States.
Youngsaye W; Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States.
Wengner A; Dana-Farber Cancer Institute, Boston, Massachusetts 01255, United States.
Kopitz C; Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States.
Lange M; Bayer AG, Berlin, Germany.
Gradl S; Bayer AG, Berlin, Germany.
Ellermann M; Bayer AG, Berlin, Germany.
Lienau P; Bayer AG, Berlin, Germany.
Schreiber SL; Bayer AG, Berlin, Germany.
Greulich H; Bayer AG, Berlin, Germany.
Meyerson M; Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States.

ACS Med Chem Lett ; 10(11): 1537-1542, 2019 Nov 14.

Article em En | MEDLINE | ID: mdl-31749907

ABSTRACT

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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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: ACS Med Chem Lett Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Estados Unidos

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