Review Article

Small molecule inhibitors targeting the PD-1/PD-L1 signaling pathway

Authors: Qian Wu1, Li Jiang1, Si-cheng Li1, Qiao-jun He1, Bo Yang1, Ji Cao1
1 Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
Correspondence to: Bo Yang: caoji88@zju.edu.cn, Ji Cao: caoji88@zju.edu.cn,
DOI: 10.1038/s41401-020-0366-x
Received: 13 October 2019
Accepted: 14 January 2020
Advance online: 9 March 2020

Abstract

Tumor cells form immune escape and subsequently obtain unlimited proliferation ability due to the abnormal immune surveillance mediated by immune checkpoints. Among this class of immune checkpoints, PD-1/PD-L1 was recognized as an anticancer drug target for many years, and so far, several monoclonal antibodies have achieved encouraging outcome in cancer treatment by targeting the PD-1/PD-L1 signaling pathway. Due to the inherent limitations of antibodies, the development of small molecule inhibitors based on PD-1/PD-L1 signaling pathway is gradually reviving in decades. In this review, we summarized a number of small molecule inhibitors based on three different therapeutic approaches interfering PD-1/PD-L1 signaling pathway: (1) blocking direct interaction between PD-1 and PD-L1; (2) inhibiting transcription and translation of PD-L1; and (3) promoting degradation of PD-L1 protein. The development of these small molecule inhibitors opens a new avenue for tumor immunotherapy based on PD-1/PD-L1 signaling pathway.
Keywords: immune checkpoints; PD-1/PD-L1; small molecule inhibitors; cancer immunotherapy

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