Discovery and Characterization of Benzamide Derivatives as Highly Potent SUCNR1 Antagonists for Cancer Immunotherapy
Zhiyuan Cheng1,2,3, Jiacheng He1,2,3, Changyao Li4
1Center for Drug Discovery & Translational Medicine, Hainan Academy of Medical Sciences, Hainan Medical University, Haikou 571199, China.
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.
Insights
Researchers developed compound 26, a novel succinate receptor 1 (SUCNR1) antagonist, to combat cancer. This compound effectively reversed immunosuppression in the tumor microenvironment and stimulated anti-tumor immune responses in preclinical models.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- The succinate receptor 1 (SUCNR1) is a critical metabolic checkpoint within the tumor microenvironment.
- Targeting SUCNR1 presents a promising avenue for advancing cancer immunotherapy strategies.
Purpose of the Study:
- To identify and develop novel SUCNR1 antagonists for cancer immunotherapy.
- To evaluate the efficacy of lead compound 26 in preclinical cancer models.
Main Methods:
- High-throughput screening of an internal library to identify hit compounds.
- Systematic structure-activity relationship (SAR) studies to optimize lead compounds.
- In vitro cell functional assays and molecular dynamics simulations.
- Evaluation in patient-derived tumor immune organoid models.
Main Results:
- Compound 26 demonstrated low-nanomolar SUCNR1 antagonistic activity.
- Molecular dynamics revealed stable interactions between compound 26 and the SUCNR1 receptor.
- Compound 26 reversed succinate-induced immunosuppression in macrophages.
- Compound 26 promoted anti-tumor immunity in organoid models, reducing immunosuppressive cells and increasing cytotoxic T cells.
Conclusions:
- Compound 26 is a potent SUCNR1 antagonist and a promising lead candidate for cancer therapy.
- SUCNR1 antagonism represents a viable therapeutic strategy in immuno-oncology.
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