Identification of the exosomal PD-L1 inhibitor to promote the PD-1 targeting therapy of gastric cancer

• Published in: European journal of medicinal chemistry 2024-03, Vol.268, p.116182-116182, Article 116182
• Main Authors: Sun, Jian-Gang, Gao, Ya, Gao, Yong-Shun, Dai, Xing-Jie, Chen, Peng
• Format: Article
• Language: English
• Subjects: CD63; Exosomes; Gastric cancer; PD-1; PD-L1
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2024.116182

Programmed death 1/programmed death-ligand 1 (PD-1/PD-L1) targeting therapy is widely applied in clinics for gastric cancer treatment. Nevertheless, the clinical response is not well acceptable due to the exosomal PD-L1. Hence, abrogation of the exosomal PD-L1 may be a strategy to sensitize the gastric cancer cell to PD-1 targeting therapy. With the aid of CD63 targeting antibody and PD-L1 targeting aptamer, HTRF based assay was established to quantify the exosomal PD-L1, and applied to our in-house compound library, resulting in the identification of moclobemide. Further optimization of moclobemide lead to EP16, which can inhibit the generation of exosomal PD-L1 with IC50 = 0.108 μM. By applying EP16 to gastric cancer cell line coupled with T-cell activity related experiment, it was validated to activate T-cell and can promote the response of PD-1 targeting therapy for gastric cancer treatment in vitro and in vivo. Collectively, our findings give a promising tool to promote the sensitivity of anti-PD-1 for gastric cancer treatment, and EP16 can serve as a leading compound for exosomal PD-L1 abrogation. [Display omitted] •EP16 was designed by using phenotype-based assay and our in-house compound library.•EP16 inhibited the generation of exosomal PD-L1 with an IC50 value of 0.108 μM.•EP16 promoted the response to PD-1/PD-L1 targeted therapy in vitro and in vivo.