Review Article

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

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:, Ji Cao:,
DOI: 10.1038/s41401-020-0366-x
Received: 13 October 2019
Accepted: 14 January 2020
Advance online: 9 March 2020


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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