Design, Synthesis and Biological Evaluation of Novel, Potent, Selective and Orally Available DGKα Inhibitors for the Treatment of Tumors
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 <b>10</b> as a novel, potent, selective, and orally available DGKα inhibitor with a promising ADME profile. More importantly, compound <b>10</b> significantly enhanced the <i>in vivo</i> antitumor activities by combination with anti-PD-1 or anti-CTLA-4 in different mouse models, and obvious synergistic effects were observed.
Authors
- Haoyu Zhang (ORCID: https://orcid.org/0000-0003-1468-862X)
- Alex Zhavoronkov (ORCID: https://orcid.org/0000-0001-7067-8966)
- Ruizheng Shi (ORCID: https://orcid.org/0000-0002-1537-4430)
- Huaxing Yu (ORCID: https://orcid.org/0000-0003-3438-3495)
- Deheng Sun (ORCID: https://orcid.org/0009-0004-0082-6918)
- Alexander Aliper (ORCID: https://orcid.org/0000-0002-4363-0710)
- Man Zhang (ORCID: https://orcid.org/0000-0001-5166-6804)
- Shan Chen (ORCID: https://orcid.org/0000-0002-6177-5980)
- Jinxin Liu (ORCID: https://orcid.org/0000-0002-5302-866X)
- Xiao Ding (ORCID: https://orcid.org/0000-0003-3482-1870)
- Xin Cai
- Hui Cui (ORCID: https://orcid.org/0009-0002-0710-6425)
- Feng Ren (ORCID: https://orcid.org/0000-0001-9157-9182)
- Hongfu Lu (ORCID: https://orcid.org/0009-0006-8111-9362)
- Sujing Shi
Institutions
- Hong Kong Science and Technology Parks Corporation (HK)
- La Jolla Alcohol Research (US)
- Insilico Medicine (United States)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-12-01
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c01943
- Citations
- 1
- Primary Topic
- Protein Kinase Regulation and GTPase Signaling
- Type
- article
- Field-Weighted Citation Impact
- 0.81