2. Academic Validation
  3. Design, synthesis, and antitumor activity evaluation of 1,2,3-triazole derivatives as potent PD-1/PD-L1 inhibitors

Design, synthesis, and antitumor activity evaluation of 1,2,3-triazole derivatives as potent PD-1/PD-L1 inhibitors

  • Bioorg Chem. 2024 Sep 7:153:107813. doi: 10.1016/j.bioorg.2024.107813.
Yu Xia 1,  Hongbo Zhang 1,  Huijie Du 1,  Lei Huang 1,  Chunqiu Yu 1,  Haozhe Wu 1,  Yiwei Zhang 1,  Yungen Xu 2,  Qihua Zhu 3,  Yi Zou 4
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China.
  • 2 Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China. Electronic address: xyg@cpu.edu.cn.
  • 3 Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China. Electronic address: zhuqihua@vip126.com.
  • 4 Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China. Electronic address: zouyi@cpu.edu.cn.
PMID: 39278065 DOI: 10.1016/j.bioorg.2024.107813
Abstract

A series of 1,2,3-triazole derivatives targeting the PD-1/PD-L1 pathway were designed, synthesized, and evaluated both in vitro and in vivo. Among them, compound III-4 demonstrated exceptional inhibitory activity against the interaction of PD-1/PD-L1 and showed great binding affinity with hPD-L1, with an IC50 value of 2.9 nM and a KD value of 3.33 nM. In the co-culture of Hep3B/OS-8/hPD-L1 cells and CD3+ T cells assay, III-4 relieved the inhibition of PD-L1 on PD-1 and promoted the expression of IFN-γ, which shared a comparable effect to that of the PD-1 monoclonal antibody Pembrolizumab (5 μg/mL). Moreover, compound III-5, an ester prodrug derived from III-4, demonstrated significant antitumor effects in the hPD-L1-MC38 C57BL/6 mouse model (TGI: 49.6 %) by oral administration. These findings suggest that compound III-5 holds promise as an inhibitor of the PD-1/PD-L1 interaction for Cancer Immunotherapy.

Keywords

1,2,3-Triazole; Cancer immunotherapy; PD-1/PD-L1; Small molecular inhibitors.

Figures
Products