2. Academic Validation
  3. Discovery of Novel, Potent, Selective, and Orally Available DGKα Inhibitors for the Treatment of Tumors

Discovery of Novel, Potent, Selective, and Orally Available DGKα Inhibitors for the Treatment of Tumors

  • J Med Chem. 2025 Sep 25;68(18):19645-19660. doi: 10.1021/acs.jmedchem.5c01944.
Hongfu Lu 1,  Deheng Sun 1,  Haoyu Zhang 1,  Sujing Shi 1,  Huaxing Yu 1,  Hui Cui 1,  Xin Cai 1,  Xiao Ding 1,  Shan Chen 1,  Man Zhang 1,  Alex Aliper 2,  Feng Ren 1 3,  Alex Zhavoronkov 1 2 3
Affiliations

Affiliations

  • 1 Insilico Medicine Shanghai Ltd, Suite 901, Tower C, Changtai Plaza, 2889 Jinke Road, Pudong New District, Shanghai 201203, China.
  • 2 Insilico Medicine AI Ltd, Masdar City, Abu Dhabi 145748, United Arab Emirates.
  • 3 Insilico Medicine Hong Kong Ltd, Hong Kong Science and Technology Park, Hong Kong 999077, China.
PMID: 40916365 DOI: 10.1021/acs.jmedchem.5c01944
Abstract

DGKα, also named diacylglycerol kinase alpha, plays an important role in signal transduction, phosphorylating the membrane lipid diacylglycerol (DAG), to phosphatidic acid (PA). Increasing evidence indicates that DGKα-mediated T-cell dysfunction plays a significant role in the development of resistance of the PD-1 blockade. In this article, we report the discovery of compound 16 as a novel, potent, orally available DGKα inhibitor with excellent kinase selectivity, a favorable ADME profile, and robust in vivo antitumor activity in combination with anti-PD-1 therapy.

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