Insights into non-peptide small-molecule inhibitors of the PD-1/PD-L1 interaction: Development and perspective. (1st March 2021)

• Record Type: Journal Article
• Authors: Wu, Xia; Meng, Yangyang; Liu, Lei; Gong, Guowei; Zhang, Haotian; Hou, Yunlei; Liu, Chunyang; Wu, Di; Qin, Mingze
• Is Part Of: Bioorganic & medicinal chemistry. Volume 33(2021)
• Publication Date: 2021-03-01
• Subjects: Cancer immunotherapy -- The PD-1/PD-L1 blockade -- Non-peptide small-molecule inhibitors -- Rational drug design; mAbs monoclonal antibodies -- PD-1 programmed cell death-1 -- PD-L1 programmed cell death-ligand 1 -- CAR-T chimeric antigen receptor T -- CTLA-4 cytotoxic T lymphocyte antigen-4 -- LAG3 lymphocyte activation gene 3 -- TIM3 T-cell membrane protein 3 -- VISTA V-domain immunoglobulin suppressor of T-cell activation -- FDA Food and Drug Administration -- Tregs regulatory T cells -- TAMs tumor-associated macrophages -- ITIM immunoreceptor tyrosine-based inhibitory motif -- ITSM immunoreceptor tyrosine-based switch motiF -- STAT3 signal transducer and activator of transcription 3 -- HIF-1a hypoxia-inducible factor alpha -- MAPK mitogen-activated protein kinase -- SHP-1 Src homology region 2 domain-containing phosphatase-1 -- TCR T-cell receptor -- IFN-γ interferon-γ -- IL-2 interleukin 2 -- hPD-1 human PD-1 -- hPD-L1 human PD-L1 -- PPI protein-protein interaction -- MSPA mouse splenocyte proliferation assay -- BMS Bristol-Myers Squibb -- HTRF homogenous time-resolved fluorescence -- NMR Nuclear magnetic resonance -- DSF differential scanning fluorimetry -- ELISA enzyme-linked immunosorbent assay -- NSCLC non-small-cell lung cancer -- PFS progression-free survival -- ORR objective response rate -- PARP Poly (adenosine diphosphate [ADP]-ribose) polymerase -- TMB tumor mutant burden -- PROTAC proteolysis targeting chimera -- LYTAC lysosome targeting chimera -- UPS ubiquitin proteasome system -- FCM flow cytometry -- CI-M6PR cation-independent mannose-6-phosphate receptor; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2021.116038
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: The development of immune checkpoint inhibitors has become a research hotspot in cancer immunotherapy in recent years. Anti-PD-1/PD-L1 monoclonal antibodies (mAbs), such as pembrolizumab and nivolumab have been approved for treating different types of cancer. Many peptides, peptidomimetics and non-peptide small-molecule inhibitors targeting the PD-1/PD-L1 axis have been published so far. In comparison with mAbs, small-molecule inhibitors have the potential to overcome inherent shortcomings of mAbs, such as poor oral bioavailability, low tumor penetration, and high manufacturing costs. In this article, we mainly review non-peptide small-molecule inhibitors of the PD-1/PD-L1 interaction, their cocrystal structures, docking studies, and biological activities are also included to guide future study. In addition, we propose several strategies for designing more effective small-molecule modulators of the PD-1/PD-L1 pathway.