2. Academic Validation
  3. Discovery of bifunctional small molecules targeting PD-L1/VISTA with favorable pharmacokinetics for cancer immunotherapy

Discovery of bifunctional small molecules targeting PD-L1/VISTA with favorable pharmacokinetics for cancer immunotherapy

  • Bioorg Chem. 2025 Mar 1:157:108323. doi: 10.1016/j.bioorg.2025.108323.
Yao Xiao 1,  Yaru Shi 2,  Chuxiao Shao 2,  Wubing Tang 3,  Hao Liu 4,  Jianjun Chen 5,  Shuanghu Wang 6,  Binbin Cheng 7
Affiliations

Affiliations

  • 1 Wuchang Hospital Affiliated to Wuhan University of Science and Technology, Wuhan Wuchang Hospital, Wuchang 430063, PR China.
  • 2 Central Laboratory, Wenzhou Medical University Lishui Hospital, Lishui People's Hospital, Lishui, Zhejiang 323000, PR China.
  • 3 Department of Oncology, The Sixth Affiliated Hospital, School of Medicine, South China University of Technology, Foshan 528200, PR China. Electronic address: lytangwb@scut.edu.cn.
  • 4 Wuchang Hospital Affiliated to Wuhan University of Science and Technology, Wuhan Wuchang Hospital, Wuchang 430063, PR China. Electronic address: 13407109890@163.com.
  • 5 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, PR China. Electronic address: jchen21@smu.edu.cn.
  • 6 Central Laboratory, Wenzhou Medical University Lishui Hospital, Lishui People's Hospital, Lishui, Zhejiang 323000, PR China. Electronic address: wangshuanghu@lsu.edu.cn.
  • 7 Central Laboratory, Wenzhou Medical University Lishui Hospital, Lishui People's Hospital, Lishui, Zhejiang 323000, PR China; Hubei Polytechnic University, Hubei Key Laboratory for Kidney Disease Pathogenesis and Intervention, Hubei Polytechnic University School of Medicine, Huangshi 435003, PR China. Electronic address: 2248549496@qq.com.
PMID: 40049048 DOI: 10.1016/j.bioorg.2025.108323
Abstract

In this work, we designed and synthesized a series of bifunctional PD-L1/VISTA (V-domain immunoglobulin suppressor of T-cell activation) small molecule inhibitors. Among them, S8 showed acceptable PD-L1 inhibitory effects (IC50 = 1.4 μM, HTRF assay) and VISTA binding activity (KD = 2.1 μM, ITC assay). BLI, ITC, and DSF assays further confirmed its dual action mode. Notably, S8 exhibited desirable in vivo pharmacokinetic properties, featuring a respectable oral bioavailability of 34.2 %. Moreover, oral administration of S8 led to a 40 % reduction in tumor weight and a 51 % decrease in tumor volume in a B16-F10 tumor model, better than the positive control an anti-PD-L1 antibody, and CA-170. PK-PD studies show that the plasma level of unbound S8 covered the biochemical IC50 concentration determined by ITC and HTRF assays, which is consistent with the strong antitumor activity observed in vivo. Analysis of tumor-infiltrating lymphocytes (TILs) via flow cytometry suggested that S8 activated the tumor immune microenvironment to exert its anti-cancer effects. In summary, S8 represents a dual PD-L1/VISTA Inhibitor with potential for further investigation as a dual-function immunotherapeutic agent.

Keywords

Bifunctional small molecules; Cancer immunotherapy; PD-1/PD-L1; VISTA.

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