Discovery of [1,2,4]Triazolo[4,3-<i>a</i>]pyridines as Potent Inhibitors Targeting the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Interaction

Qin, Mingze; Cao, Qi; Zheng, Shuaishuai; Tian, Ye; Zhang, Haotian; Xie, Jun; Xie, Hongbo; Liu, Yajing; Zhao, Yanfang; Gong, Ping

doi:10.1021/acs.jmedchem.9b00312

Cited by 84 publications

(72 citation statements)

References 23 publications

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“…The further residue contribution comparison (Figure S6) and conformational analysis (Figure S7) of the residues within 5 angstroms showed that the residues interacting with R-group substituents had an obvious effect on the docking scores including B Asp122 (interacting with R1 to R3) and A Asp122, A Lys124, B Tyr56, B Gln66 (interacting with R4 to R7). The binding mode analysis of novel series of [1,2,4]triazolo[4,3-a]pyridines designed by Qin et al also revealed the retaining hydrophobic interaction with Tyr56, Met115, and Ala121 on both chain of PD-L1 and extra π-π stacking with the B Tyr56 and π-anion interactions with A Asp122 (Qin et al, 2019). These interacting modes of [1,2,4]triazolo[4,3-a]pyridines inhibitors were consistent with the binding mode analysis of eight representative small-molecule inhibitors.…”

Section: Resultsmentioning

confidence: 99%

Computational Insight Into the Small Molecule Intervening PD-L1 Dimerization and the Potential Structure-Activity Relationship

Shi

Bai

et al. 2019

Front. Chem.

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Recently, small-molecule compounds have been reported to block the PD-1/PD-L1 interaction by inducing the dimerization of PD-L1. All these inhibitors had a common scaffold and interacted with the cavity formed by two PD-L1 monomers. This special interactive mode provided clues for the structure-based drug design, however, also showed limitations for the discovery of small-molecule inhibitors with new scaffolds. In this study, we revealed the structure-activity relationship of the current small-molecule inhibitors targeting dimerization of PD-L1 by predicting their binding and unbinding mechanism via conventional molecular dynamics and metadynamics simulation. During the binding process, the representative inhibitors (BMS-8 and BMS-1166) tended to have a more stable binding mode with one PD-L1 monomer than the other and the small-molecule inducing PD-L1 dimerization was further stabilized by the non-polar interaction of Ile54, Tyr56, Met115, Ala121, and Tyr123 on both monomers and the water bridges involved in ALys124. The unbinding process prediction showed that the PD-L1 dimerization kept stable upon the dissociation of ligands. It's indicated that the formation and stability of the small-molecule inducing PD-L1 dimerization was the key factor for the inhibitory activities of these ligands. The contact analysis, R-group based quantitative structure-activity relationship (QSAR) analysis and molecular docking further suggested that each attachment point on the core scaffold of ligands had a specific preference for pharmacophore elements when improving the inhibitory activities by structural modifications. Taken together, the results in this study could guide the structural optimization and the further discovery of novel small-molecule inhibitors targeting PD-L1.

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Section: Resultsmentioning

confidence: 99%

Computational Insight Into the Small Molecule Intervening PD-L1 Dimerization and the Potential Structure-Activity Relationship

Shi

Bai

et al. 2019

Front. Chem.

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“…These two approaches led to the identification of the promising lead compound 79 with an IC 50 value of 92.3 nM established with the HTRF binding assay. Additionally, 79 induced the IFN-γ secretion in a T cell-tumor co-culture model of the Hep3B/OS-8/hPD-L1 and CD3 T cells [88].…”

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

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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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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“…One of the key structural features of BMS compounds is the biphenyl moiety, which is also observed in subsequently reported PD‐1/PD‐L1 inhibitors. For example, Gong et al reported a biphenyl‐containing compound A22 inhibiting PD‐1/PD‐L1 interaction with an IC 50 value of 92.3 nmol·L −1 in vitro (Qin et al, 2019). Furthermore, Basu et al reported that the biphenyl‐containing compound 2b blocked PD1/PDL1 interaction with an IC 50 value of 3.0 nmol·L −1 in a homogeneous time resolved fluorescence (HTRF) assay (Basu et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Discovery of a novel, potent and selective small‐molecule inhibitor of PD‐1/PD‐L1 interaction with robust in vivo anti‐tumour efficacy

Liu

Zhou

Yan

et al. 2021

British J Pharmacology

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Background and purpose PD‐1/PD‐L1 antibodies have achieved great success in clinical treatment. However, monoclonal antibody drugs also have challenges, such as high manufacturing costs, poor diffusion, low oral bioavailability and limited penetration into tumour tissue. The development of small‐molecule inhibitors of PD‐1/PD‐L1 interaction represents a promising perspective to overcome the above challenges in cancer immunotherapy. Experimental approach We explored structural activity relationships and used biochemical assays to generate a lead compound (ZE132). CD8+ T‐cells killing assay and Ifng expression assay were used to verify the in vitro cellular activity of ZE132. Off‐target study was performed to verify the selectivity. Syngeneic mouse models were used to verify the in vivo activity of ZE132 in tumour immune microenvironment (TIME). We also performed pharmacokinetics profiling in mice and The Cancer Genome Atlas database analysis. Key results ZE132 can effectively inhibit the PD‐1/PD‐L1 interactions in vitro, and it has a potent affinity to PD‐L1. ZE132 shows robust anti‐tumour effects in vivo, better than anti‐PD‐1 antibody. In the analysis of TIME, we found that ZE132 treatment promotes cytotoxic T‐cell tumour infiltration and induces IL‐2 expression. In addition, ZE132 elicits strong inhibitory effects on the mRNA expression of TGF‐β, which may serve as a potential biomarker to predict responsiveness to PD‐1/PD‐L1 immunotherapies. Conclusion and implications We identified a new lead compound ZE132 targeting PD‐1/PD‐L1 interactions, not only showing favourable drug‐like properties in vitro and in vivo but also showing the advantage of overcoming the barrier of TIME compared to anti‐PD‐1 antibody.

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Discovery of [1,2,4]Triazolo[4,3-a]pyridines as Potent Inhibitors Targeting the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Interaction

Cited by 84 publications

References 23 publications

Computational Insight Into the Small Molecule Intervening PD-L1 Dimerization and the Potential Structure-Activity Relationship

Computational Insight Into the Small Molecule Intervening PD-L1 Dimerization and the Potential Structure-Activity Relationship

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

Discovery of a novel, potent and selective small‐molecule inhibitor of PD‐1/PD‐L1 interaction with robust in vivo anti‐tumour efficacy

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