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
  • 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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