Discovery of Potent, Dual-Inhibitors of Diacylglycerol Kinases Alpha and Zeta Guided by Phenotypic Optimization
Louis Chupak, Michael Wichroski, Xiaofan Zheng, Min Ding, Scott Martin, Christopher B. Allard, Jianliang Shi, Robert G. Gentles, Nicholas A. Meanwell, Jie Fang, Daniel J. Tenney, John S. Tokarski, Carolyn Cao, Susan Wee
Abstract
We describe a phenotypic screening and optimization strategy to discover compounds that block intracellular checkpoint signaling in T-cells. We identified dual DGKα and ζ inhibitors notwithstanding the modest similarity between α and ζ relative to other DGK isoforms. Optimized compounds produced cytokine release and T-cell proliferation consistent with DGK inhibition and potentiated an immune response in human and mouse T-cells. Additionally, lead inhibitor BMS-502 demonstrated dose-dependent immune stimulation in the mouse OT-1 model, setting the stage for a drug discovery program.