Discovery and Characterization of Benzamide Derivatives as Highly Potent SUCNR1 Antagonists for Cancer Immunotherapy.

Targeting the succinate receptor 1 (SUCNR1), a key metabolic checkpoint in the tumor microenvironment, emerges as a promising strategy for cancer immunotherapy. Herein, we identified a weak benzamide-based hit compound (5) through an internal library screening. A systematic structure-activity relationship (SAR) exploration then yielded compound 26, which exhibited low-nanomolar SUCNR1 antagonistic activity in multiple cell functional assays. Molecular dynamics simulations revealed that the methoxy group of 26 forms stable, water-bridged hydrogen bonds with the key residue Glu221.31. Notably, 26 effectively reversed succinate-mediated immunosuppression in macrophages by abrogating the expression of multiple immunosuppression-related genes. In the patient-derived tumor immune organoid models, 26 triggered a robust antitumor immune response, marked by a reduction in immunosuppressive macrophages and a concomitant expansion of cytotoxic T cells. Thus, our work not only establishes 26 as a lead candidate for targeting SUCNR1 but also provides compelling evidence for SUCNR1 antagonism as a potent therapeutic approach in immuno-oncology.