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

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

  • ACS Med Chem Lett. 2023 Jun 12;14(7):929-935. doi: 10.1021/acsmedchemlett.3c00063.
Louis Chupak 1,  Michael Wichroski 1,  Xiaofan Zheng 1,  Min Ding 1,  Scott Martin 1,  Christopher Allard 1,  Jianliang Shi 2,  Robert Gentles 1,  Nicholas A Meanwell 2,  Jie Fang 2,  Daniel Tenney 2,  John Tokarski 2,  Carolyn Cao 2,  Susan Wee 2
Affiliations

Affiliations

  • 1 Bristol Myers Squibb Research and Early Development, 100 Binney Street, Cambridge, Massachusetts 02142, United States.
  • 2 Bristol Myers Squibb Research and Early Development, PO Box 4000, Princeton, New Jersey 08543-4000, United States.
PMID: 37465293 DOI: 10.1021/acsmedchemlett.3c00063
Abstract

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.

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