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

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

  • Bioorg Chem. 2026 Mar:170:109477. doi: 10.1016/j.bioorg.2026.109477.
Xuewen Zhang 1,  Lirong Zhang 1,  Zhiqiang Sun 2,  Chenglong Xu 1,  Jiamin Tan 1,  Yichang Ren 1,  Jian Zhang 3,  Ting Chen 4,  Zhijie Wang 5,  Dulin Kong 6,  Jianjun Chen 7
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory of New Drug Screening, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
  • 2 The Seventh Affiliated Hospital, Southern Medical University, Foshan 528244, China.
  • 3 Guangdong Provincial Key Laboratory of New Drug Screening, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China; Department of Pharmaceutical and Artificial-Intelligence Sciences, Institute of Artificial Intelligence for Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: [email protected].
  • 4 Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, China. Electronic address: [email protected].
  • 5 Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou 450046, China. Electronic address: [email protected].
  • 6 Engineering Research Center of Tropical Medicine Innovation and Transformation of Ministry of Education, International Joint Research Center of Human-Machine Intelligent Collaborative for Tumor Precision Diagnosis and Treatment of Hainan Province, Hainan Provincial Key Laboratory of Research and Development on Tropical Herbs, School of Pharmaceutical Sciences, Hainan Medical University, Haikou 571199, China. Electronic address: [email protected].
  • 7 Guangdong Provincial Key Laboratory of New Drug Screening, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China; The Seventh Affiliated Hospital, Southern Medical University, Foshan 528244, China. Electronic address: [email protected].
PMID: 41529601 DOI: 10.1016/j.bioorg.2026.109477
Abstract

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.

Keywords

Immunotherapy; PD-1/PD-L1 inhibitors; Pyrrolopyridine.

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