Design, Synthesis, and T Cell Checkpoint Combination Potential Of First-In-Class DGKα/ζ Inhibitor BMS-986408

DGKα and DGKζ are intracellular T cell checkpoints that negatively regulate T cell signaling, activation, and tumor immunity. Inhibition of DGKα/ζ is an attractive mechanism for next-generation immunotherapy, with the potential to broaden the response to existing cancer treatments, including anti-PD-1 and anti-CTLA-4. The lead molecule BMS-502 was optimized to the first-in-class dual DGKα/ζ inhibitor BMS-986408 (BMS-408), starting with the replacement of an aryl nitro group that posed a potential liability. Subsequent improvement in cellular potency, cross-species oral pharmacokinetic profile, and optimization of physicochemical properties led to the identification of the development candidate BMS-408. In preclinical studies, BMS-408 demonstrated dose-proportional pharmacokinetics and pharmacodynamics in mice, as well as robust efficacy in combination with either anti-PD-1 and/or anti-CTLA-4 in MC-38 and 1956 tumor models. Given the favorable in vitro and in vivo profiles, as well as in vivo pharmacology, BMS-408 was advanced to clinical development.