2. Academic Validation
  3. Discovery of Small Molecule PD-L1 Inhibitors via Optimization of Solvent-Interaction Region for Cancer Immunotherapy

Discovery of Small Molecule PD-L1 Inhibitors via Optimization of Solvent-Interaction Region for Cancer Immunotherapy

  • Chem Biol Drug Des. 2025 Jun;105(6):e70141. doi: 10.1111/cbdd.70141.
Binbin Cheng 1 2,  Ting Liu 3,  Hao Cao 4,  Jin Liu 2,  Yichang Ren 2,  Junli Huang 2,  Dulin Kong 5,  Ting Chen 6,  Yong Liu 7,  Jianjun Chen 2
Affiliations

Affiliations

  • 1 School of Medicine, Hubei Polytechnic University, Huangshi, China.
  • 2 School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou, China.
  • 3 Longhua District People's Hospital of Shenzhen, Shenzhen, China.
  • 4 Department of Medicine, People's Hospital of Xiangzhou District, Zhuhai, Guangdong, P. R. China.
  • 5 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, China.
  • 6 Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
  • 7 Department of Intensive Care Unit, Shenzhen Hospital, Southern Medical University, Shenzhen, China.
PMID: 40490909 DOI: 10.1111/cbdd.70141
Abstract

Despite extensive research, the topic of anti-PD-L1 small-molecule inhibitors remains elusive. Herein, we report the design, synthesis, and bioevaluation of a series of small molecule PD-L1 inhibitors via optimization of the solvent-interaction region. Among them, compound GJ19 showed the most potent anti-PD-L1 effects with an IC50 of 32.06 nM in the HTRF (homogenous time-resolved fluorescence) assay, better than BMS-202 (IC50 = 62.1 nM). In addition, the SPR (surface plasmon resonance) assay revealed that GJ19 can effectively bind to human/murine PD-L1 protein with KD values of 171 and 290 nM, respectively. Furthermore, GJ19 concentration-dependently promoted HepG2 cell mortality in a co-culture model of HepG2/hPD-L1 and Jurkat T/hPD-1 cells. In the in vivo efficacy studies, GJ19 (intraperitoneal injection, 15 mg/kg) effectively suppressed tumor growth with a TGI of 56.8% in a B16-F10 melanoma mouse model by activating antitumor immunity. In conclusion, GJ19 represents a potential small molecule inhibitor of PD-L1, deserving further investigation for tumor immunotherapy.

Keywords

cancer immunotherapy; small molecule PD‐L1 inhibitor; solvent‐interaction region.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-174830
    PDL1 Inhibitor