2. Academic Validation
  3. Recent advance of peptide-based molecules and nonpeptidic small-molecules modulating PD-1/PD-L1 protein-protein interaction or targeting PD-L1 protein degradation

Recent advance of peptide-based molecules and nonpeptidic small-molecules modulating PD-1/PD-L1 protein-protein interaction or targeting PD-L1 protein degradation

  • Eur J Med Chem. 2021 Mar 5:213:113170. doi: 10.1016/j.ejmech.2021.113170.
Chenghao Pan 1,  Haiyan Yang 2,  Yang Lu 1,  Shengquan Hu 1,  Yizhe Wu 1,  Qiaojun He 3,  Xiaowu Dong 4
Affiliations

Affiliations

  • 1 Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China.
  • 2 Department of Lymphoma, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, 310012, PR China; Institute of Cancer and Basic Medicine (IBMC), Chinese Academy of Sciences, Hangzhou, 310000, PR China.
  • 3 Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China; Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou, 310058, PR China; Cancer Center of Zhejiang University, Hangzhou, 310058, PR China. Electronic address: qiaojunhe@zju.edu.cn.
  • 4 Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China; Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou, 310058, PR China; Cancer Center of Zhejiang University, Hangzhou, 310058, PR China. Electronic address: dongxw@zju.edu.cn.
PMID: 33454550 DOI: 10.1016/j.ejmech.2021.113170
Abstract

Tumor immunotherapy has made great progress in recent years. In the tumor microenvironment, the binding of PD-1 and its ligand PD-L1 can promote tumor immune escape and tumor survival. Clinical studies have indicated that Antibodies blocking PD-1 and PD-L1 have reliable effects on many advanced malignant tumors. However, no small-molecule inhibitors have been approved so far, indicating that the development of marketable small-molecules PD-1/PD-L1 targeted therapy drugs is a challenging process. Small-molecule inhibitors can overcome the limitations of monoclonal Antibodies, including poor oral bioavailability, high cost, poor tissue and tumor penetration and long half-life, which prompt researchers to turn their attention to the development of peptide molecules and small-molecule inhibitors modulating PD-1/PD-L1 to overcome some disadvantages of monoclonal Antibodies or targeting PD-L1 protein degradation as potential alternatives or supplements. In this review, we will focus on the peptide-based and nonpeptidic molecules against PD-1/PD-L1 base on the structural classification. More importantly, we also focus on the latest research progress of small-molecules mediated PD-L1 degradation mechanism.

Keywords

PD-1/PD-L1 small-molecule inhibitors; PD-L1 degradation mechanism; Tumor immunotherapy.

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