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PD-1/PD-L1 Inhibitors for Immuno-oncology: From Antibodies to Small Molecules

[ Vol. 23 , Issue. 39 ]


Qiaohong Geng, Peifu Jiao*, Peng Jin, Gaoxing Su, Jinlong Dong and Bing Yan*   Pages 6033 - 6041 ( 9 )


Background: The recent regulatory approvals of immune checkpoint protein inhibitors, such as ipilimumab, pembrolizumab, nivolumab, atezolizumab, durvalumab, and avelumab ushered a new era in cancer therapy. These inhibitors do not attack tumor cells directly but instead mobilize the immune system to re-recognize and eradicate tumors, which endows them with unique advantages including durable clinical responses and substantial clinical benefits. PD-1/PD-L1 inhibitors, a pillar of immune checkpoint protein inhibitors, have demonstrated unprecedented clinical efficacy in more than 20 cancer types. Besides monoclonal antibodies, diverse PD- 1/PD-L1 inhibiting candidates, such as peptides, small molecules have formed a powerful collection of weapons to fight cancer.

Methods: The goal of this review is to summarize and discuss the current PD-1/PD-L1 inhibitors including candidates under clinical development, their molecular interactions with PD-1 or PD-L1, the disclosed structureactivity relationships of peptides and small molecules as inhibitors.

Results: Current PD-1/PD-L1 inhibitors under clinical development are exclusively dominated by antibodies. The molecular interactions of therapeutic antibodies with PD-1 or PD-L1 have been gradually elucidated for the design of novel inhibitors. Various peptides and traditional small molecules have been investigated in preclinical model to discover novel PD-1/PD-L1 inhibitors.

Conclusion: Peptides and small molecules may play an important role in immuno-oncology because they may bind to multiple immune checkpoint proteins via rational design, opening opportunity for a new generation of novel PD-1/PD-L1 inhibitors.


Cancer immunotherapy, therapeutic antibody, small molecules, peptides, structure-activity relationships, tumor cells.


Department of Chemistry, Qilu Normal University, Jinan, Shandong 250013, Department of Chemistry, Qilu Normal University, Jinan, Shandong 250013, Department of Chemistry, Qilu Normal University, Jinan, Shandong 250013, School of Pharmacy, Nantong University, Nantong, Jiangsu 226001, Jinan Taorui Pharma & Tech Co., Ltd., Jinan, Shandong 250101, School of Environmental Science and Engineering, Shandong University, Jinan, Shandong 250100

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