Advances of Biphenyl Small-Molecule Inhibitors Targeting PD-1/PD-L1 Interaction in Cancer Immunotherapy

Chen, Roufen; Yuan, Dandan; Ma, Junjie

doi:10.4155/fmc-2021-0256

Cited by 12 publications

(11 citation statements)

References 53 publications

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“…Two years ago, we initiated in silico analyses of drug-PD-L1 binding with a series of molecules containing a biphenyl unit, as found in the reference products BMS- 202 and BMS-1166 previously characterized as potent PD-L1 binders [14]. The biphenyl core is an essential element for the binding of the molecules at the interface of the PD-L1 dimeric structure [31]. Different biphenylcontaining molecules binding to PD-L1 were identified, such as the anti-inflammatory drugs flurbiprofen, for example [21].…”

Section: Molecular Modeling Of Pd-l1/kya1797k Bindingmentioning

confidence: 99%

A Potential Off-Target Effect of the Wnt/β-Catenin Inhibitor KYA1797K: PD-L1 Binding and Checkpoint Inhibition

et al. 2023

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Introduction: The quest for small molecule inhibitors of the PD-1/PD-L1 checkpoint continues in parallel to the extensive development of monoclonal antibodies directed against this immune checkpoint. Drug screening strategies are being set up to identify novel PD-L1 inhibitors. Methods: A virtual screening based on molecular docking with the PD-L1 protein dimer has been performed to identify a new binder. Binding of the identified ligand to PD-L1 has been validated experimentally using a microscale thermophoresis (MST) assay. The cellular effect of the compound was evidenced using a fluorescence resonance energy transfer (FRET) assay based on activation of tyrosine phosphatase SHP-2. Results: We have identified the potent Wnt/β-catenin inhibitor KYA1797K as a weak PD-L1 binder. Molecular docking suggested that the compound can bind to the interface of a PD-L1 dimer, with a geometry superimposable to that of the reference PD-L1 inhibitor BMS-202. The atypical 2-thioxo-4-thiazolidinone motif of KYA1797K, derived from the natural product rhodanine, plays a major role in the interaction with PD-L1. Binding of KYA1797K to recombinant hPD-L1 was validated experimentally, using MST. The drug was found to bind modestly but effectively to hPD-L1. The FRET assay confirmed the weak capacity of KYA1797K to interfere with the activation of SHP-2 upon its interaction with human PD-1. Discussion: Collectively, the data show that KYA1797K could function as a weak modulator of the PD-1/PD-L1 checkpoint. This effect may contribute, at least partially, to the reported capacity of the β-catenin inhibitor to downregulate PD-L1 in cancer cells. The work also underlines the interest to further consider the rhodanine moiety as a chemical motif for the design of new PD-L1 binders.

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Section: Molecular Modeling Of Pd-l1/kya1797k Bindingmentioning

confidence: 99%

A Potential Off-Target Effect of the Wnt/β-Catenin Inhibitor KYA1797K: PD-L1 Binding and Checkpoint Inhibition

et al. 2023

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“…Up- or down-regulators of PD-L1 expression have been identified from compound libraries, including natural products, kinase inhibitors, checkpoint degraders, etc. [ 115 , 116 , 117 , 118 ]. Several approved drugs have been characterized as well for their capacity to regulate expression and function of PD-1/PD-L1.…”

Section: Drug Repositioning To Target the Pd-1/pd-l1 Checkpointmentioning

confidence: 99%

Drug Repurposing to Enhance Antitumor Response to PD-1/PD-L1 Immune Checkpoint Inhibitors

Thuru

Magnez

El-Bouazzati

et al. 2022

Cancers

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Monoclonal antibodies targeting the PD-1/PD-L1 immune checkpoint have considerably improved the treatment of some cancers, but novel drugs, new combinations, and treatment modalities are needed to reinvigorate immunosurveillance in immune-refractory tumors. An option to elicit antitumor immunity against cancer consists of using approved and marketed drugs known for their capacity to modulate the expression and functioning of the PD-1/PD-L1 checkpoint. Here, we have reviewed several types of drugs known to alter the checkpoint, either directly via the blockade of PD-L1 or indirectly via an action on upstream effectors (such as STAT3) to suppress PD-L1 transcription or to induce its proteasomal degradation. Specifically, the repositioning of the approved drugs liothyronine, azelnidipine (and related dihydropyridine calcium channel blockers), niclosamide, albendazole/flubendazole, and a few other modulators of the PD-1/PD-L1 checkpoint (repaglinide, pimozide, fenofibrate, lonazolac, propranolol) is presented. Their capacity to bind to PD-L1 or to repress its expression and function offer novel perspectives for combination with PD-1 targeted biotherapeutics. These known and affordable drugs could be useful to improve the therapy of cancer.

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“…Most of these PD-L1-targeted small molecules contain a biphenyl core, and function by inducing PD-L1 dimerization [ 7 , 8 , 9 ]. Different structural archetypes have been reported, including pyrazolo-pyridine derivatives [ 10 ], phenylindoline derivatives [ 11 ], triazine-based molecules [ 12 ] and various biphenyl compounds [ 13 , 14 ]. Potent compounds have been designed, with nanomolar affinities toward PD-L1, but only a very few have reached phase 1 clinical development [ 4 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

Antioxidant Properties and Aldehyde Reactivity of PD-L1 Targeted Aryl-Pyrazolone Anticancer Agents

et al. 2022

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Small molecules targeting the PD-1/PD-L1 checkpoint are actively searched to complement the anticancer arsenal. Different molecular scaffolds have been reported, including phenyl-pyrazolone derivatives which potently inhibit binding of PD-L1 to PD-1. These molecules are structurally close to antioxidant drug edaravone (EDA) used to treat amyotrophic lateral sclerosis. For this reason, we investigated the capacity of five PD-L1-binding phenyl-pyrazolone compounds (1–5) to scavenge the formation of oxygen free radicals using electron spin resonance spectroscopy with DPPH/DMPO probes. In addition, the reactivity of the compounds toward the oxidized base 5-formyluracil (5fU) was assessed using chromatography coupled to mass spectrometry and photodiode array detectors. The data revealed that the phenyl-pyrazolone derivatives display antioxidant properties and exhibit a variable reactivity toward 5fU. Compound 2 with a N-dichlorophenyl-pyrazolone moiety cumulates the three properties, being a potent PD-L1 binder, a robust antioxidant and an aldehyde-reactive compound. On the opposite, the adamantane derivative 5 is a potent PD-L1 binding with a reduced antioxidant potential and no aldehyde reactivity. The nature of the substituent on the phenyl-pyrazolone core modulates the antioxidant capacity and reactivity toward aromatic aldehydes. The molecular signature of the compound can be adapted at will, to confer additional properties to these PD-L1 binders.

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Advances of Biphenyl Small-Molecule Inhibitors Targeting PD-1/PD-L1 Interaction in Cancer Immunotherapy

Cited by 12 publications

References 53 publications

A Potential Off-Target Effect of the Wnt/β-Catenin Inhibitor KYA1797K: PD-L1 Binding and Checkpoint Inhibition

A Potential Off-Target Effect of the Wnt/β-Catenin Inhibitor KYA1797K: PD-L1 Binding and Checkpoint Inhibition

Drug Repurposing to Enhance Antitumor Response to PD-1/PD-L1 Immune Checkpoint Inhibitors

Antioxidant Properties and Aldehyde Reactivity of PD-L1 Targeted Aryl-Pyrazolone Anticancer Agents

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