2. Academic Validation
  3. Discovery and Characterization of Benzamide Derivatives as Highly Potent SUCNR1 Antagonists for Cancer Immunotherapy

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

  • J Med Chem. 2026 Jun 25;69(12):14174-14190. doi: 10.1021/acs.jmedchem.5c03465.
Zhiyuan Cheng 1 2 3,  Jiacheng He 1 2 3,  Changyao Li 4,  Ke Quan 3,  Limin Du 5,  Xiaolei Chai 3,  Xinyu Yang 3,  Naijipu Abuduaini 6,  Yuanyuan Fu 3,  Jing Sun 6,  Sen Zhang 6,  Bo Feng 6,  Deyan Wu 7,  Weiwei Rui 6,  H Eric Xu 4 8,  Linlin Yang 5,  Mingyao Liu 1 2 3,  Weiqiang Lu 1 2 3 9
Affiliations

Affiliations

  • 1 Center for Drug Discovery & Translational Medicine, Hainan Academy of Medical Sciences, Hainan Medical University, Haikou 571199, China.
  • 2 Engineering Research Center of Tropical Medicine Innovation and Transformation of Ministry of Education, Hainan Provincial Key Laboratory for Research and Development of Tropical Herbs and Haikou Key Laboratory of Li Nationality Medicine, School of Pharmaceutical Sciences, Hainan Medical University, Haikou 571199, China.
  • 3 Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
  • 4 Research Center for Medicinal Structural Biology, National Research Center for Translational Medicine at Shanghai, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200020, China.
  • 5 Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450052, China.
  • 6 Department of General Surgery and Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200020, China.
  • 7 School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China.
  • 8 The State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 9 State Key Laboratory of Innovative Immunotherapy, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai 200240, China.
PMID: 42101162 DOI: 10.1021/acs.jmedchem.5c03465
Abstract

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.

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