Development of Inhibitors of the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Signaling Pathway

Wang, Tianyu; Wu, Xiaoxing; Guo, Cui; Zhang, Kuojun; Xu, Jinyi; Li, Zheng; Jiang, Sheng

doi:10.1021/acs.jmedchem.8b00990

Cited by 99 publications

(69 citation statements)

References 80 publications

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“…Peptides and peptidomimetics can be considered the binding bridge between antibodies and small-molecular inhibitors targeting the PD-1/PD-L1 immune checkpoint. The companies Aurigene Discovery Technologies Limited and Pierre Fabre started a cooperation to design new cancer therapeutics in immune-oncology in 2014, which resulted in the structure of AUNP12 ( 1 ) (Figure 1), an immune checkpoint modulator targeting the PD-1/PD-L1 pathway [33,35]. AUNP-12 is a 29-mer peptide and is highly active in HEK293 cells expressing hPD-L2 (EC 50 of 0.72 nM).…”

Section: Inhibitors Of the Pd-1/pd-l1 Interactionmentioning

confidence: 99%

“…Until now, among all disclosed compounds, only one small molecule inhibitor (CA-170, see below) and a macrocyclic peptide (BMS-986189) have proceeded to clinical trial. Within the last few years, several reviews have summarized the progress on the development of peptidic and small-molecule inhibitors of the PD-1/PD-L1 axis with their structural aspects [4,29,30,31,32,33,34]. Herein, we review the most recent advancements in the field of the design and protein interaction of small-molecule inhibitors of the PD-1/PD-L1 interaction.…”

Section: Introductionmentioning

confidence: 99%

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Development of the Inhibitors That Target the PD-1/PD-L1 Interaction—A Brief Look at Progress on Small Molecules, Peptides and Macrocycles

et al. 2019

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Cancer immunotherapy based on antibodies targeting the immune checkpoint PD-1/PD-L1 pathway has seen unprecedented clinical responses and constitutes the new paradigm in cancer therapy. The antibody-based immunotherapies have several limitations such as high production cost of the antibodies or their long half-life. Small-molecule inhibitors of the PD-1/PD-L1 interaction have been highly anticipated as a promising alternative or complementary therapeutic to the monoclonal antibodies (mAbs). Currently, the field of developing anti-PD-1/PD-L1 small-molecule inhibitors is intensively explored. In this paper, we review anti-PD-1/PD-L1 small-molecule and peptide-based inhibitors and discuss recent structural and preclinical/clinical aspects of their development. Discovery of the therapeutics based on small-molecule inhibitors of the PD-1/PD-L1 interaction represents a promising but challenging perspective in cancer treatment.

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Section: Inhibitors Of the Pd-1/pd-l1 Interactionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Development of the Inhibitors That Target the PD-1/PD-L1 Interaction—A Brief Look at Progress on Small Molecules, Peptides and Macrocycles

et al. 2019

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“…However, the promise of superior pharmacokinetic properties of small molecule drugs, greater flexibility of administration through different routes, and superior stability and cost-effectiveness has revitalized efforts to replace antibodies with confirmed therapeutic impact with small molecules that mimic antibody binding and functionality [90]. Proof-of-concept for the clinical potential of the approach comes, for instance, from attempts of small molecule-targeting of the PD-1/PD-L1 pathway for cancer therapy [91] and the nAb epitope-informed design of a small molecule alternative to a broadly neutralizing anti-influenza virus antibody directed against the HA stem domain [92]. Given the dramatic expansion in high-resolution structural insight in productive nAb-F protein interaction in recent years, it will be exciting to see whether this knowledge can be equally harnessed for the structure-guided development of new classes of pneumo-and paramyxovirus entry inhibitors.…”

Section: Druggable Sites and Neutralizing Epitopesmentioning

confidence: 99%

Structural Insight into Paramyxovirus and Pneumovirus Entry Inhibition

Aggarwal

Plemper

2020

Viruses

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Paramyxoviruses and pneumoviruses infect cells through fusion (F) protein-mediated merger of the viral envelope with target membranes. Members of these families include a range of major human and animal pathogens, such as respiratory syncytial virus (RSV), measles virus (MeV), human parainfluenza viruses (HPIVs), and highly pathogenic Nipah virus (NiV). High-resolution F protein structures in both the metastable pre-and the postfusion conformation have been solved for several members of the families and a number of F-targeting entry inhibitors have progressed to advanced development or clinical testing. However, small-molecule RSV entry inhibitors have overall disappointed in clinical trials and viral resistance developed rapidly in experimental settings and patients, raising the question of whether the available structural information may provide a path to counteract viral escape through proactive inhibitor engineering. This article will summarize current mechanistic insight into F-mediated membrane fusion and examine the contribution of structural information to the development of small-molecule F inhibitors. Implications are outlined for future drug target selection and rational drug engineering strategies.Viruses 2020, 12, 342 2 of 16 from its natural bat host to domestic animals, resulting in case/fatality rates reaching from 40% to over 90% [9]. Continued spillover into the human population must be expected, and human-to-human transmission through respiratory secretions, urine, and saliva has been documented [10].Of the pneumoviruses, RSV infects almost all children before two years of age and is responsible for over 100,000 hospitalizations yearly in the United States alone. The monoclonal antibody palivizumab has been approved for immunoprophylaxis against RSV infection [11], however, use is restricted to high-risk patients due to the high-cost and need for prophylactic administration.Given the health, medical and economic burden associated with paramyxo-and pneumovirus infections, a major and currently unmet clinical need exists to expedite the development of novel safe and effective therapeutics for improved disease management and outbreak control. Current direct-acting therapeutics predominantly focus on preventing viral entry through neutralizing antibodies (nAbs) and on small-molecules targeting the envelope glycoproteins or inhibiting the viral RNA-dependent RNA polymerase (RdRP) complex. Reflecting major efforts to identify a cost-effective alternative to high-price passive immunization with anti-RSV nAbs, a number of compounds have entered advanced preclinical development and clinical testing in recent years (Table 1). Breakthroughs in the structural and functional characterization of the viral entry machinery and polymerase complexes in the past decade [12][13][14][15][16][17][18][19][20][21] have furthermore created a novel opportunity for structure-informed mechanistic characterization and ligand optimization.

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“…In a panel of functional assays, CA-170 showed selectivity against other immune checkpoint pathways including CTLA4, LAG3, and BTLA. These non-clinical data provided a strong rationale for the clinical development of CA-170 [30][31][32].…”

Section: Introductionmentioning

confidence: 97%

Identification of active small-molecule modulators targeting the novel immune checkpoint VISTA

Jiang

Qie³

et al. 2020

Preprint

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Background: Cancer immunotherapy has gained increasing popularity as a novel approach to treat cancer. A member of the B7 family, V-domain immunoglobulin suppressor of T-cell activation (VISTA) is a novel immune checkpoint that regulates a broad spectrum of immune responses. VISTA is an acidic pH-selective ligand for P-selectin glycoprotein ligand-1(PSGL-1). CA-170, a first-in-class small-molecule dual antagonist of VISTA/PD-L1, was collaboratively developed by Aurigene Discovery Technologies Limited and Curis, Inc. It is currently in Phase I clinical trial.Results: In this study, we develop homology modeling for the VISTA 3D structure and subsequent virtual screening for VISTA small-molecule hit ligands. Visualization of the binding postures of docked ligands with the VISTA protein indicates that some small molecular compounds target VISTA. The ability of antagonist to disrupt immune checkpoint VISTA pathways was investigated though functional studies in vitro.Conclusions: Affinity active molecule for VISTA was obtained through virtual screening, and the antagonist compound activity to VISTA was assayed in cellular level. We reported a small molecule with high VISTA affinity as antagonist , providing ideas for development VISTA-targeted small molecule compound in cancer immunotherapy.

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Development of Inhibitors of the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Signaling Pathway

Cited by 99 publications

References 80 publications

Development of the Inhibitors That Target the PD-1/PD-L1 Interaction—A Brief Look at Progress on Small Molecules, Peptides and Macrocycles

Development of the Inhibitors That Target the PD-1/PD-L1 Interaction—A Brief Look at Progress on Small Molecules, Peptides and Macrocycles

Structural Insight into Paramyxovirus and Pneumovirus Entry Inhibition

Identification of active small-molecule modulators targeting the novel immune checkpoint VISTA

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