2. Academic Validation
  3. Design, synthesis, anti-tumor activity and mechanism of novel PROTACs as degraders of PD-L1 and inhibitors of PD-1/PD-L1 interaction

Design, synthesis, anti-tumor activity and mechanism of novel PROTACs as degraders of PD-L1 and inhibitors of PD-1/PD-L1 interaction

  • Bioorg Med Chem. 2024 Sep 1:111:117867. doi: 10.1016/j.bmc.2024.117867.
Feng Zhang 1,  Qimeng Yu 1,  Caiyun Wu 1,  Shishi Sun 1,  Yu Wang 1,  Rui Wang 1,  Zejie Chen 1,  Hua Zhang 1,  Xuqiong Xiong 1,  Annoor Awadasseid 2,  Guowu Rao 3,  Xiaoyin Zhao 4,  Wen Zhang 5
Affiliations

Affiliations

  • 1 College of Pharmaceutical Science, Zhejiang University of Technology, Deqing 313299, China; Institute of Drug Development & Chemical Biology, Zhejiang University of Technology, Deqing 313299, China.
  • 2 College of Pharmaceutical Science, Zhejiang University of Technology, Deqing 313299, China; Institute of Drug Development & Chemical Biology, Zhejiang University of Technology, Deqing 313299, China; Moganshan Institute, Zhejiang University of Technology, Deqing 313200, China.
  • 3 College of Pharmaceutical Science, Zhejiang University of Technology, Deqing 313299, China; Institute of Drug Development & Chemical Biology, Zhejiang University of Technology, Deqing 313299, China. Electronic address: rgw@zjut.edu.cn.
  • 4 College of Pharmaceutical Science, Zhejiang University of Technology, Deqing 313299, China; Institute of Drug Development & Chemical Biology, Zhejiang University of Technology, Deqing 313299, China. Electronic address: zhaoxiaoyin@zjut.edu.cn.
  • 5 College of Pharmaceutical Science, Zhejiang University of Technology, Deqing 313299, China; Institute of Drug Development & Chemical Biology, Zhejiang University of Technology, Deqing 313299, China; Zhejiang Jieyuan Med-Tech Co., Ltd., Hangzhou 311113, China. Electronic address: wzhang63@zjut.edu.cn.
PMID: 39121678 DOI: 10.1016/j.bmc.2024.117867
Abstract

Currently, antibody drugs targeting programmed cell death ligand 1 (PD-L1) have achieved promising results in Cancer treatment, while the development of small-molecule drugs lags behind. In this study, we designed and synthesized a series of PD-L1-degrading agents based on the PROTAC design principle, utilizing the PD-L1 inhibitor A56. Through systematic screening of ligands and linkers and investigating the structure-activity relationship of the degraders, we identified two highly active compounds, 9i and 9j. These compounds enhance levels of CD4+, CD8+, granzyme B, and perforin, demonstrating significant in vivo antitumor effects with a tumor growth inhibition (TGI) of up to 57.35 %. Both compounds facilitate the internalization of PD-L1 from the cell surface and promote its degradation through proteasomal and lysosomal pathways, while also maintaining inhibition of the PD-1/PD-L1 interaction. In summary, our findings provide a novel strategy and mechanism for developing biphenyl-based PROTAC antitumor drugs targeting and degrading PD-L1.

Keywords

Cancer; Degrader; Internalization; PD-L1; PROTAC.

Figures
Products