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.