Novel Selenium-Containing Small Molecule PD-L1 Inhibitors: Design, Synthesis, and Evaluation of the Antitumor Activity

  • J Med Chem. 2026 Jul 23;69(14):16677-16703. doi: 10.1021/acs.jmedchem.6c00363.
Jianwei Wang  1  2 ,  Shenwei Yu  1  2 ,  Liang Qian  1  2 ,  Jacek Plewka  3 ,  Ruyue Ni  1  2 ,  Chenyang Wang  1  2 ,  Feng Zhang  1  2 ,  Zeyu Chen  1  2 ,  Annoor Awadasseid  1  2  4 ,  Yanling Wu  5 ,  Katarzyna Magiera-Mularz  3 ,  Wen Zhang  1  2  6
Affiliations
  • 1. Lab of Chemical Biology and Molecular Drug Design, College of Pharmaceutical Science, Zhejiang University of Technology, Deqing 313299, China.
  • 2. Institute of Drug Development & Chemical Biology, Zhejiang University of Technology, Deqing 313299, China.
  • 3. Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Krakow, Poland.
  • 4. Kecheng Industrial Development Institute, Zhejiang University of Technology, Quzhou 324000, China.
  • 5. Hangzhou Qingzhenghong Technology Co., Ltd, Hangzhou 311121, China.
  • 6. Zhejiang Jieyuan Med-Tech Co., Ltd., Hangzhou 311113, China.
PMID: 42394434 DOI: 10.1021/acs.jmedchem.6c00363
Abstract

Novel selenium-containing small molecule PD-L1 inhibitors were designed and synthesized for the first time to explore their potential as antitumor agents. By computer-aided structural optimization, HTRF and SPR techniques, compound SA13 was identified as the most potent blocker of the PD-1/PD-L1 interaction, exhibiting an IC50 value of 5.2 ± 0.5 nM, a KD value of 9.06 ± 1.25 nM, respectively. Study on the SA13/hPD-L1 cocrystal structure (2.9 Å) revealed a unique selenomethyl-involved binding mode, which may interpret its superior inhibitory activity compared to Other analogs. Cell-based assays showed that SA13 can mediate the internalization of PD-L1 and strongly block hPD-1 and hPD-L1 interaction, demonstrating its effectiveness in biological events. Notably, in the Hu-PD-L1 MC38 mouse model, SA13 significantly inhibited tumor growth, with a tumor growth inhibition (TGI) rate of 77.79% (60 mg/kg, administrated intragastrically) with no observable toxicity. These data indicate that SA13 is a promising and safe novel antitumor agent worthy of further development.

Keywords
PD-L1 inhibitor; anti-tumor activity; selenium-containing compound; small molecule; structural optimization.
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