Discovery of Potent, Dual-Inhibitors of Diacylglycerol Kinases Alpha and Zeta Guided by Phenotypic Optimization.

Autor:	Chupak L; Bristol Myers Squibb Research and Early Development, 100 Binney Street, Cambridge, Massachusetts 02142, United States., Wichroski M; Bristol Myers Squibb Research and Early Development, 100 Binney Street, Cambridge, Massachusetts 02142, United States., Zheng X; Bristol Myers Squibb Research and Early Development, 100 Binney Street, Cambridge, Massachusetts 02142, United States., Ding M; Bristol Myers Squibb Research and Early Development, 100 Binney Street, Cambridge, Massachusetts 02142, United States., Martin S; Bristol Myers Squibb Research and Early Development, 100 Binney Street, Cambridge, Massachusetts 02142, United States., Allard C; Bristol Myers Squibb Research and Early Development, 100 Binney Street, Cambridge, Massachusetts 02142, United States., Shi J; Bristol Myers Squibb Research and Early Development, PO Box 4000, Princeton, New Jersey 08543-4000, United States., Gentles R; Bristol Myers Squibb Research and Early Development, 100 Binney Street, Cambridge, Massachusetts 02142, United States., Meanwell NA; Bristol Myers Squibb Research and Early Development, PO Box 4000, Princeton, New Jersey 08543-4000, United States., Fang J; Bristol Myers Squibb Research and Early Development, PO Box 4000, Princeton, New Jersey 08543-4000, United States., Tenney D; Bristol Myers Squibb Research and Early Development, PO Box 4000, Princeton, New Jersey 08543-4000, United States., Tokarski J; Bristol Myers Squibb Research and Early Development, PO Box 4000, Princeton, New Jersey 08543-4000, United States., Cao C; Bristol Myers Squibb Research and Early Development, PO Box 4000, Princeton, New Jersey 08543-4000, United States., Wee S; Bristol Myers Squibb Research and Early Development, PO Box 4000, Princeton, New Jersey 08543-4000, United States.
Jazyk:	angličtina
Zdroj:	ACS medicinal chemistry letters [ACS Med Chem Lett] 2023 Jun 12; Vol. 14 (7), pp. 929-935. Date of Electronic Publication: 2023 Jun 12 (Print Publication: 2023).
DOI:	10.1021/acsmedchemlett.3c00063
Abstrakt:	We describe a phenotypic screening and optimization strategy to discover compounds that block intracellular checkpoint signaling in T-cells. We identified dual DGKα and ζ inhibitors notwithstanding the modest similarity between α and ζ relative to other DGK isoforms. Optimized compounds produced cytokine release and T-cell proliferation consistent with DGK inhibition and potentiated an immune response in human and mouse T-cells. Additionally, lead inhibitor BMS-502 demonstrated dose-dependent immune stimulation in the mouse OT-1 model, setting the stage for a drug discovery program. Competing Interests: The authors declare no competing financial interest. (© 2023 American Chemical Society.)
Databáze:	MEDLINE
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