2. Academic Validation
  3. Discovery of Fluoroalkenes as Dual Inhibitors of Diacylglycerol Kinases Alpha and Zeta (DGKα/ζ)

Discovery of Fluoroalkenes as Dual Inhibitors of Diacylglycerol Kinases Alpha and Zeta (DGKα/ζ)

  • J Med Chem. 2025 Oct 9;68(19):20789-20813. doi: 10.1021/acs.jmedchem.5c02098.
Ming Xiang 1,  Shicheng Shi 1,  Shaoqun Qian 1,  Chengtsung Lai 1,  Kelly Federowicz 1,  Guofeng Zhang 1,  Melissa Chan 1,  David Rodrigues 1,  Bihui Melidosian 1,  Jeff Jackson 1,  Gengjie Yang 1,  Maryanne Covington 1,  Lisa Truong 1,  Michelle Frascella 1,  Rodrigo Hess 1,  Patrick Mayes 1,  Xiaodi Ren 1,  Sunkyu Kim 1,  Joshua R Hummel 1,  Xiaozhao Wang 1
Affiliations

Affiliation

  • 1 Incyte Research Institute, Incyte Corporation, 1801 Augustine Cut-Off, Wilmington, Delaware 19803, United States.
PMID: 40974316 DOI: 10.1021/acs.jmedchem.5c02098
Abstract

Diacylglycerol kinases alpha and zeta (DGKα/ζ) are negative regulators of T cell receptor signaling that suppress immune system activation. As such, dual inhibition of DGKα and ζ represents a promising strategy to enhance antitumor immunity, making these kinases attractive targets for Cancer Immunotherapy. Herein, we report the discovery of a series of fluoroalkenes as potent dual inhibitors of DGKα and ζ. A high-throughput screening campaign identified amide 1 with micromolar activity against DGKζ. While SAR studies revealed amides with potent dual DGKα/ζ activity, replacing the amide with a fluoroalkene bioisostere led to a significant improvement in cellular activity. Systematic SAR studies led to the discovery of lead compound 17, a potent dual DGKα/ζ inhibitor with balanced in vitro ADME properties and favorable pharmacokinetic profiles. The in vivo functional activity of compound 17 was demonstrated in an OT-1 pharmacodynamic murine model, showing robust and dose-dependent immune activation in the presence of antigen presentation.

Figures
Products