2. Academic Validation
  3. Design, Synthesis and Biological Evaluation of Novel, Potent, Selective and Orally Available DGKα Inhibitors for the Treatment of Tumors

Design, Synthesis and Biological Evaluation of Novel, Potent, Selective and Orally Available DGKα Inhibitors for the Treatment of Tumors

  • J Med Chem. 2025 Dec 11;68(23):25011-25025. doi: 10.1021/acs.jmedchem.5c01943.
Hongfu Lu 1,  Sujing Shi 1,  Huaxing Yu 1,  Deheng Sun 1,  Haoyu Zhang 1,  Hui Cui 1,  Xin Cai 1,  Xiao Ding 1,  Shan Chen 1,  Man Zhang 1,  Jinxin Liu 1,  Ryan Shi 2,  Alex Aliper 3,  Feng Ren 1 4,  Alex Zhavoronkov 1 3 4
Affiliations

Affiliations

  • 1 Insilico Medicine Shanghai Ltd, Suite 901, Tower C, Changtai Plaza, 2889 Jinke Road, Pudong New District, Shanghai 201203, China.
  • 2 The Bishop's School, 7607 La Jolla Blvd, La Jolla, California 92037, United States.
  • 3 Insilico Medicine AI Ltd, Masdar City, Abu Dhabi 145748, UAE.
  • 4 Insilico Medicine Hong Kong Ltd, Hong Kong Science and Technology Park, Hong Kong 999077, China.
PMID: 41320919 DOI: 10.1021/acs.jmedchem.5c01943
Abstract

The diacylglycerol kinase alpha (DGKα) is an important player in signal transduction, phosphorylating the membrane lipid diacylglycerol to phosphatidic acid. Emerging data indicate that DGKα mediates T cell dysfunction during anti-PD-1 therapy, having a marked impact on the development of resistance to PD-1 blockade. Here, we report the discovery of compound 10 as a novel, potent, selective, and orally available DGKα inhibitor with a promising ADME profile. More importantly, compound 10 significantly enhanced the in vivo antitumor activities by combination with anti-PD-1 or anti-CTLA-4 in different mouse models, and obvious synergistic effects were observed.

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