Advances of biphenyl small-molecule inhibitors targeting PD-1/PD-L1 interaction in cancer immunotherapy

2021 ◽  
Author(s):  
Roufen Chen ◽  
Dandan Yuan ◽  
JunJie Ma
Keyword(s):  
Monoclonal Antibodies ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Biological Activities ◽  
Treatment Strategies ◽  
Structural Features ◽  
Great Promise ◽  
Programmed Death ◽  
Programmed Death 1 ◽  
High Production Cost

Immunotherapy inhibiting the programmed death-1/programmed death ligand-1 (PD-1/PD-L1) interaction has emerged as one of the most attractive cancer treatment strategies. So far, the clinically used PD-1/PD-L1 inhibitors are monoclonal antibodies, but monoclonal antibodies have several limitations, such as poor pharmacokinetic properties, unchecked immune responses and high production cost. The development of small-molecule inhibitors targeting PD-1/PD-L1 interaction is showing great promise as a potential alternative or complementary therapeutic approach of monoclonal antibodies. In this article, the authors classify the reported biphenyl small-molecule inhibitors into symmetrical and asymmetrical types based on their structural features and further review their representative inhibitors and biological activities, as well as the binding models for providing insight into further exploration of more potent biphenyl small-molecule inhibitors targeting PD-1/PD-L1 interaction.

scholarly journals Small molecule inhibitors against PD-1/PD-L1 immune checkpoints and current methodologies for their development: a review

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Chang Liu ◽  
Navindra P. Seeram ◽  
Hang Ma
Keyword(s):  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Clinical Success ◽  
Immune Checkpoints ◽  
Biochemical Assays ◽  
Programmed Death ◽  
Blocking Effects ◽  
Programmed Death 1 ◽  
Screening Assays ◽  
Leading Compounds

AbstractProgrammed death-1/programmed death ligand-1 (PD-1/PD-L1) based immunotherapy is a revolutionary cancer therapy with great clinical success. The majority of clinically used PD-1/PD-L1 inhibitors are monoclonal antibodies but their applications are limited due to their poor oral bioavailability and immune-related adverse effects (irAEs). In contrast, several small molecule inhibitors against PD-1/PD-L1 immune checkpoints show promising blockage effects on PD-1/PD-L1 interactions without irAEs. However, proper analytical methods and bioassays are required to effectively screen small molecule derived PD-1/PD-L1 inhibitors. Herein, we summarize the biophysical and biochemical assays currently employed for the measurements of binding capacities, molecular interactions, and blocking effects of small molecule inhibitors on PD-1/PD-L1. In addition, the discovery of natural products based PD-1/PD-L1 antagonists utilizing these screening assays are reviewed. Potential pitfalls for obtaining false leading compounds as PD-1/PD-L1 inhibitors by using certain binding bioassays are also discussed in this review.

Generation and Characterization of Four Novel Monoclonal Antibodies Against Human Programmed Death-1 Molecule

Hybridoma ◽  
2010 ◽  
Vol 29 (2) ◽  
pp. 153-160 ◽  
Author(s):  
Yongjing Chen ◽  
Zhenhua Hu ◽  
Qin Wang ◽  
Yan Ge ◽  
Lixiong Bai ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Programmed Death ◽  
Programmed Death 1

Tetralone scaffolds and their potential therapeutic applications

2020 ◽  
Vol 17 ◽  
Author(s):  
Bhagwati Gauni ◽  
Krunal Mehariya ◽  
Anamik Shah ◽  
Srinivas Murty Duggirala
Keyword(s):  
Antitumor Activity ◽  
Organic Synthesis ◽  
Small Molecule ◽  
Heterocyclic Compounds ◽  
Biological Activities ◽  
Acetylcholinesterase Inhibitors ◽  
Building Blocks ◽  
Structural Features ◽  
Therapeutic Applications ◽  
Small Molecule Library

: Substituted tetralones have played a substantial role in organic synthesis due to their strong reactivity and suitability as a starting material for a range of synthetic heterocyclic compounds, pharmaceuticals along with biological activities as well as precursors of many natural products and their derivatives. Many α-tetralone derivatives are building blocks, that have been used in the synthesis of therapeutically functional compounds like some antibiotics, antidepressants, acetylcholinesterase inhibitors effective for treating Alzheimer’s disease and alkaloids possessing antitumor activity. In this review, there has been an attempt to explore the small molecule library having α-tetralone scaffold along with their diverse biological activities. Structural features of α-tetralone derivatives responsible for potential therapeutic applications are also described.

scholarly journals Small molecule inhibitors of divalent metal transporter-1

2009 ◽  
Vol 296 (4) ◽  
pp. G798-G804 ◽  
Author(s):  
Peter D. Buckett ◽  
Marianne Wessling-Resnick
Keyword(s):  
Small Molecule ◽  
Iron Metabolism ◽  
Iron Uptake ◽  
Small Molecule Inhibitors ◽  
Structural Features ◽  
Divalent Metal ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Copper Chelation ◽  
Metal Transporter

Divalent metal transporter-1 (DMT1) is a divalent cation transporter that plays a key role in iron metabolism by mediating ferrous iron uptake across the small intestine. We have previously identified several small molecule inhibitors of iron uptake ( 4 ). Using a cell line that stably overexpresses DMT1, we screened the ability of these inhibitors to specifically block this transporter's activity. One compound, NSC306711, inhibited DMT1-mediated iron uptake in a reversible and competitive manner. This inhibitor is a polysulfonated dye containing two copper centers. Although one of these two sites could be chelated by Triethylenetetramine copper chelation did not perturb NSC306711 inhibition of DMT1 activity. Several other polysulfonated dyes with structural features similar to NSC306711 were identified as potential DMT1 transport inhibitors. This study characterizes important pharmacological tools that can be used to probe DMT1's mechanism of iron transport and its role in iron metabolism.

scholarly journals Evolving Pharmacotherapies for the Treatment of Metastatic Melanoma

2013 ◽  
Vol 7 ◽  
pp. CMO.S9565 ◽  
Author(s):  
April K.S. Salama
Keyword(s):  
Metastatic Melanoma ◽  
Cytotoxic T Lymphocyte ◽  
Great Promise ◽  
Targeted Agents ◽  
Immune Modulators ◽  
Programmed Death ◽  
Programmed Death 1 ◽  
Long Term Survivors ◽  
Systemic Therapies

Metastatic melanoma remains a difficult disease to treat, and long term survivors are rare. Over the past few years, however, breakthroughs in both immunotherapy as well as targeted agents have had a tremendous impact on patients diagnosed with this disease. This review summarizes recent advances in systemic therapies for melanoma, including immune modulators directed against cytotoxic T lymphocyte associated antigen-4 (CTLA-4) and programmed death-1 (PD-1), as well as a number of targeted agents. These approaches hold great promise as the landscape of therapeutic options for advanced melanoma continues to evolve.

Peptide and small molecule inhibitors of the Keap1–Nrf2 protein–protein interaction

2015 ◽  
Vol 43 (4) ◽  
pp. 674-679 ◽  
Author(s):  
Geoff Wells
Keyword(s):  
Small Molecule ◽  
Protein Interaction ◽  
Small Molecule Inhibitors ◽  
Biological Activities ◽  
Cancer Chemoprevention ◽  
Antioxidant Response ◽  
Related Factor ◽  
Promoter Regions ◽  
Protein Protein Interaction ◽  
Antioxidant Response Elements

The transcription factor nuclear factor erythroid-2-related factor 2 (Nrf2) up-regulates the expression of a range of cytoprotective enzymes with antioxidant response elements in their promoter regions and thus can protect cells against oxidative damage. Increasing Nrf2 activity has been proposed as a therapeutic intervention in a range of chronic neurodegenerative conditions and cancer chemoprevention. One of the main mechanisms by which Nrf2 is negatively regulated involves an interaction with the ubiquitination facilitator protein, Kelch-like ECH-associated protein 1 (Keap1) that facilitates degradation of Nrf2. Inhibition of this process underlies the mode of action of a broad group of compounds that increase Nrf2 activity. A number of natural products, including the isothiocyanate sulforaphane, up-regulate Nrf2 by interacting with Keap1 in a covalent manner to stall its activity. Recently, a number of peptide and small molecule inhibitors of the protein-protein interaction (PPI) between Keap1 and Nrf2 have been described. These classes of compound have contrasting modes of action at the molecular level and there is emerging evidence that their biological activities have similarities and differences. This review describes the various classes of PPI inhibitor that have been described in the literature and the biological evaluations that have been performed.

scholarly journals Nephrotoxicity in patients with solid tumors treated with anti-PD-1/PD-L1 monoclonal antibodies: a systematic review and meta-analysis

2021 ◽  
Author(s):  
Han Li ◽  
Jinsheng Xu ◽  
Yaling Bai ◽  
Shenglei Zhang ◽  
Meijuan Cheng ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Solid Tumors ◽  
Meta Analysis ◽  
Kidney Injury ◽  
Cochrane Library ◽  
Randomized Controlled ◽  
Programmed Death ◽  
Registration Number ◽  
Programmed Death 1 ◽  
The Cochrane Library

SummaryBackground Programmed death-1 (PD-1) and programmed death ligand 1 (PD-L1) have dramatically improved cancer therapy for many patients. Adverse kidney effects have been found to be an important complication but have unclear mechanisms. Methods We searched Embase, PubMed, and the Cochrane Library to identify potential eligible studies. All included studies were randomized controlled trials (RCTs) examining patients with solid tumors treated with anti-PD-1/PD-L1 monoclonal antibodies (mAbs) and/or chemotherapy. The relative risk (RR) was used to assess the risk of nephrotoxic events. Results We included 27 clinical trials (15,063 patients). Compared with chemotherapy, the RR of all-grade nephritis was significantly increased with anti-PD-1/PD-L1 mAbs (RR = 2.77, 95% CI: 1.09–6.99, P = 0.03). Furthermore, anti-PD-1/PD-L1 mAbs plus chemotherapy can significantly increase the RR of all-grade nephritis (RR = 2.99, 95% CI: 1.07–8.35, P = 0.04). There was also a significant increase in the RRs of all-grade increased blood creatinine (RR = 1.88, 95% CI: 1.24–2.86, P = 0.003) and acute kidney injury (AKI) (RR =3.35, 95% CI: 1.48–7.60, P = 0.004). Conclusions Anti-PD-1/PD-L1 mAbs can significantly increase nephrotoxicity in patients with solid tumors, especially when combined with chemotherapy. During the application of these drugs, we should remain aware of nephrotoxicity for better efficacy. Trial registration number and date of registration Not applicable.

scholarly journals A Small Molecule Antagonist of PD-1/PD-L1 Interactions Acts as an Immune Checkpoint Inhibitor for NSCLC and Melanoma Immunotherapy

2021 ◽  
Vol 12 ◽  
Author(s):  
Yuanyuan Wang ◽  
Tingxuan Gu ◽  
Xueli Tian ◽  
Wenwen Li ◽  
Ran Zhao ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Monoclonal Antibodies ◽  
Small Molecule ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Small Molecule Antagonist ◽  
Programmed Death

Immune checkpoint inhibitors, such as monoclonal antibodies targeting programmed death 1 (PD-1) and programmed death ligand-1 (PD-L1), have achieved enormous success in the treatment of several cancers. However, monoclonal antibodies are expensive to produce, have poor tumor penetration, and may induce autoimmune side effects, all of which limit their application. Here, we demonstrate that PDI-1 (also name PD1/PD-L1 inhibitor 1), a small molecule antagonist of PD-1/PD-L1 interactions, shows potent anti-tumor activity in vitro and in vivo and acts by relieving PD-1/PD-L1-induced T cell exhaustion. We show that PDI-1 binds with high affinity to purified human and mouse PD-1 and PD-L1 proteins and is a competitive inhibitor of human PD-1/PD-L1 binding in vitro. Incubation of ex vivo activated human T cells with PDI-1 enhanced their cytotoxicity towards human lung cancer and melanoma cells, and concomitantly increased the production of granzyme B, perforin, and inflammatory cytokines. Luciferase reporter assays showed that PDI-1 directly increases TCR-mediated activation of NFAT in a PD-1/PD-L1-dependent manner. In two syngeneic mouse tumor models, the intraperitoneal administration of PDI-1 reduced the growth of tumors derived from human PD-L1-transfected mouse lung cancer and melanoma cells; increased and decreased the abundance of tumor-infiltrating CD8+ and FoxP3+ CD4+ T cells, respectively; decreased the abundance of PD-L1-expressing tumor cells, and increased the production of inflammatory cytokines. The anti-tumor effect of PDI-1 in vivo was comparable to that of the anti-PD-L1 antibody atezolizumab. These results suggest that the small molecule inhibitors of PD-1/PD-L1 may be effective as an alternative or complementary immune checkpoint inhibitor to monoclonal antibodies.

Sign in / Sign up

Export Citation Format

Share Document