Discovery of Small-Molecule Inhibitors of the PD-1/PD-L1 Axis That Promote PD-L1 Internalization and Degradation

Wang, Tianyu; Cai, Shi; Cheng, Yao; Zhang, Wanheng; Wang, Minmin; Sun, Huiyong; Guo, Binghua; Li, Zheng; Xiao, Yibei; Jiang, Sheng

doi:10.1021/acs.jmedchem.1c01682

Cited by 78 publications

(63 citation statements)

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“…These 13 PDB structures were described in six peer‐reviewed journal publications by a number of research groups focused on discovering and developing orally bioavailable, small‐molecule drugs as alternatives to monoclonal antibody immune checkpoint anti‐cancer therapies. 107 , 108 , 109 , 110 , 111 , 112 , 113 Such ligands are thought to reduce tumor immune evasion via small molecule‐induced dimerization PD‐L1 and subsequent internalization. This effect on the immune checkpoint is mechanistically distinct from that of anti‐PD‐1 and anti‐PD‐L1 monoclonal antibodies, which interdict PD‐1/PD‐L1 mediated interactions between T‐cells and tumor cells.…”

Section: Resultsmentioning

confidence: 99%

RCSB Protein Data bank: Tools for visualizing and understanding biological macromolecules in 3D

Burley

Bhikadiya

et al. 2022

Protein Science

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Now in its 52nd year of continuous operations, the Protein Data Bank (PDB) is the premiere open‐access global archive housing three‐dimensional (3D) biomolecular structure data. It is jointly managed by the Worldwide Protein Data Bank (wwPDB) partnership. The Research Collaboratory for Structural Bioinformatics Protein Data Bank (RCSB PDB) is funded by the National Science Foundation, National Institutes of Health, and US Department of Energy and serves as the US data center for the wwPDB. RCSB PDB is also responsible for the security of PDB data in its role as wwPDB‐designated Archive Keeper. Every year, RCSB PDB serves tens of thousands of depositors of 3D macromolecular structure data (coming from macromolecular crystallography, nuclear magnetic resonance spectroscopy, electron microscopy, and micro‐electron diffraction). The RCSB PDB research‐focused web portal (http://RCSB.org) makes PDB data available at no charge and without usage restrictions to many millions of PDB data consumers around the world. The RCSB PDB training, outreach, and education web portal (http://PDB101.RCSB.org) serves nearly 700 K educators, students, and members of the public worldwide. This invited Tools Issue contribution describes how RCSB PDB (i) is organized; (ii) works with wwPDB partners to process new depositions; (iii) serves as the wwPDB‐designated Archive Keeper; (iv) enables exploration and 3D visualization of PDB data via http://RCSB.org; and (v) supports training, outreach, and education via http://PDB101.RCSB.org. New tools and features at http://RCSB.org are presented using examples drawn from high‐resolution structural studies of proteins relevant to treatment of human cancers by targeting immune checkpoints.

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Section: Resultsmentioning

confidence: 99%

RCSB Protein Data bank: Tools for visualizing and understanding biological macromolecules in 3D

Burley

Bhikadiya

et al. 2022

Protein Science

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“…Additionally, it was found that the binding of a biphenyl inhibitor to PD-L1 at the early stages of protein maturation suppresses protein glycosylation and prevents the transport of the under-glycosylated form of PD-L1 from the endoplasmic reticulum to the Golgi apparatus [131]. A recent report showed that the internalized PD-L1 is subjected to lysosome-dependent degradation triggered by biphenyl inhibitors (Figure 16) [132]. Based on the unique internalization and degradation mechanism of biphenyl-based small molecule inhibitors, derived radioligands could theoretically offer the possibility for an endoradiotherapy approach with beta-or alpha-emitting nuclides.…”

Section: Discussion and Outlookmentioning

confidence: 98%

Development of Radiotracers for Imaging of the PD-1/PD-L1 Axis

2022

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Immune checkpoint inhibitor (ICI) therapy has emerged as a major treatment option for a variety of cancers. Among the immune checkpoints addressed, the programmed death receptor 1 (PD-1) and its ligand PD-L1 are the key targets for an ICI. PD-L1 has especially been proven to be a reproducible biomarker allowing for therapy decisions and monitoring therapy success. However, the expression of PD-L1 is not only heterogeneous among and within tumor lesions, but the expression is very dynamic and changes over time. Immunohistochemistry, which is the standard diagnostic tool, can only inadequately address these challenges. On the other hand, molecular imaging techniques such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT) provide the advantage of a whole-body scan and therefore fully address the issue of the heterogeneous expression of checkpoints over time. Here, we provide an overview of existing PET, SPECT, and optical imaging (OI) (radio)tracers for the imaging of the upregulation levels of PD-1 and PD-L1. We summarize the preclinical and clinical data of the different molecule classes of radiotracers and discuss their respective advantages and disadvantages. At the end, we show possible future directions for developing new radiotracers for the imaging of PD-1/PD-L1 status in cancer patients.

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“…Recently, Wang et al reported a discovery of a PD-1/PD-L1 small molecular inhibitor, which induced the dimerization of PD-L1, which was internalized into the cytosol, and degraded through a lysosome-dependent pathway 66 . From this point of view, inducing the formation of PD-L1 dimer would be a good strategy to reduce the concentration of PD-L1 and inhibit PD-1/PD-L1 pathway.…”

Section: Comparison Between the In Vitro Ic50 Of Camp On Pd-1/pd-l1 B...mentioning

confidence: 99%

Study on endogenous inhibitors against PD-L1: cAMP as a potential candidate

Huang

Zang

Zhang

et al. 2022

Preprint

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The discovery of new anticancer drugs targeting the PD-1/PD-L1 pathway has been research hotspots. In this study, a combination of biological affinity ultrafiltration (BAU), UPLC-HRMS, molecular dynamic (MD) simulations and molecular docking methods were applied to search for endogenous active compounds that can inhibit the binding of PD-L1 and PD-1. We screened dozens of potential cancer related endogenous compounds. The results showed that cyclic adenosine monophosphate (cAMP) had a direct inhibition effect on the PD-1/PD-L1 binding with an in vitro IC50 value of about 2.7 uM determined by homogeneous time-resolved fluorescence (HTRF) assay. The binding mode analyses for the cAMP - dimeric/monomeric PD-L1 complex indicated that cAMP was likely to bind to the dimeric PD-L1, since the binding free energies of the cAMP - dimeric and monomeric PD-L1 complex were about 23.6 and 15.1 kcal/mol, respectively, from MD simulations. The direct binding assay using surface plasmon resonance (SPR) method showed that cAMP could also bind to monomeric PD-L1 fixed on the sensor chip surface with a KD value of about 1.72 mM. Our findings suggested that cAMP may directly inhibit the PD-1/PD-L1 interaction.

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Discovery of Small-Molecule Inhibitors of the PD-1/PD-L1 Axis That Promote PD-L1 Internalization and Degradation

Cited by 78 publications

References 50 publications

RCSB Protein Data bank: Tools for visualizing and understanding biological macromolecules in 3D

RCSB Protein Data bank: Tools for visualizing and understanding biological macromolecules in 3D

Development of Radiotracers for Imaging of the PD-1/PD-L1 Axis

Study on endogenous inhibitors against PD-L1: cAMP as a potential candidate

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