Discovery of PD-L1 inhibitors featuring novel indole and pyrrolopyridine scaffolds with PD-L1 degradation activity in vivo.

To broaden the structural diversity of contemporary small molecule PD-L1 inhibitors, we rationally designed and synthesized a novel series of PD-L1 targeting compounds based on the structural features of the known lead compound 24, incorporating indole and pyrrolopyridine scaffolds. Among these, compound Z38 emerged as the most potent candidate, with a half maximal inhibitory concentration (IC₅₀) of 110 nM against PD-L1 and significantly lower cytotoxicity than the lead compound. Z38 exerted dose dependent immunomodulatory effects in a HepG2/Jurkat T cell coculture system, promoting HepG2 cell death by restoring T cell mediated antitumor immunity. In B16-F10 melanoma bearing mice, intraperitoneal administration of Z38 (30 mg/kg) achieved a tumor growth inhibition rate (TGI) of 60 % without detectable organ toxicity. Mechanistically, Z38 activated the tumor immune microenvironment by increasing tumor infiltrating lymphocytes (TILs) and inducing ∼50 % PD-L1 degradation in tumor tissues. This work identifies Z38 as a structurally distinct, low toxicity PD-L1 inhibitor with robust in vitro and in vivo antitumor efficacy, offering a promising lead for further development.