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

Leleu-Chavain, Natascha; Regnault, Romain; Ahouari, Hania; Biannic, Raphaël Le; Kouach, Mostafa; Klupsch, Frédérique; Magnez, Romain; Vezin, Hervé; Thuru, Xavier; Bailly, Christian; Goossens, Jean‐François; Millet, Régis

doi:10.3390/molecules27103316

Cited by 4 publications

(6 citation statements)

References 52 publications

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“…The methodology is well adapted to identify small molecule modulators of PPIs, offering a rapid screening approach. We have found the method particularly well-suited to characterize small molecule interrupters of immune checkpoints, be it the PD-1/PD-L1 checkpoint or other checkpoints such as TIM-3/galectin-9 [ 72 , 73 , 86 ]. It is clearly one of the best biophysical methods in early drug discovery [ 108 ].…”

Section: Discussionmentioning

confidence: 99%

“…Different pharma companies, such as Bristol−Myers Squibb (BMS) and Aurigene (US), are intensely implicated in the design and development of small molecule PD-L1 binders, and for that they have used MST to characterize the PD-L1 binding capacity of the molecules [ 71 ]. Many academic groups are also implicated in the race to find new PD-L1 binders, including our group with the recent discovery of a category of pyrazolone-type molecules [ 72 , 73 ]. Several biophysical methods such as MST, SPR and ITC can be used to evaluate PD-L1 binding of such small molecules.…”

Section: Case Studiesmentioning

confidence: 99%

“… * Compounds from BMS, as described in [ 66 ]. ** Pyrazolone derivatives, recently designed and characterized [ 72 , 73 ]. …”

Section: Figurementioning

confidence: 99%

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Microscale Thermophoresis as a Tool to Study Protein Interactions and Their Implication in Human Diseases

Magnez

Bailly

Thuru

2022

IJMS

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The review highlights how protein–protein interactions (PPIs) have determining roles in most life processes and how interactions between protein partners are involved in various human diseases. The study of PPIs and binding interactions as well as their understanding, quantification and pharmacological regulation are crucial for therapeutic purposes. Diverse computational and analytical methods, combined with high-throughput screening (HTS), have been extensively used to characterize multiple types of PPIs, but these procedures are generally laborious, long and expensive. Rapid, robust and efficient alternative methods are proposed, including the use of Microscale Thermophoresis (MST), which has emerged as the technology of choice in drug discovery programs in recent years. This review summarizes selected case studies pertaining to the use of MST to detect therapeutically pertinent proteins and highlights the biological importance of binding interactions, implicated in various human diseases. The benefits and limitations of MST to study PPIs and to identify regulators are discussed.

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Section: Discussionmentioning

confidence: 99%

Section: Case Studiesmentioning

confidence: 99%

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Microscale Thermophoresis as a Tool to Study Protein Interactions and Their Implication in Human Diseases

Magnez

Bailly

Thuru

2022

IJMS

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“…For our part, we have exploited two complementary approaches. On the one hand, we set up a biophysical method based on microscale thermophoresis (MST) to characterize drug-PD-L1 interaction and to guide the design of new binders [6,18,19]. On the other hand, we set up a molecular docking approach, based on a deconvolution of the biphenyl scaffold originally proposed by BMS, to identify new potential PD-L1 binders [20][21][22].…”

Section: Introductionmentioning

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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“…Some of our phenyl-pyrazolone derivatives cumulate the properties of EDA as antioxidant and aldehyde-reactive molecules, in addition to their inhibitory action toward PD-L1. Indeed, we have shown recently that the phenyl-pyrazolone compounds 2 and 3 (Figure 1) combine the three desired properties: (i) a tight binding to PD-L1, (ii) a scavenging of oxygen free radicals and (iii) a covalent binding to 5-formyluracil used as a model aldehyde [17]. In an extension of this drug design program, we now report the synthesis and properties of two new phenyl-pyrazolone derivatives selected for their improved properties.…”

Section: Introductionmentioning

confidence: 99%

Novel PD-L1-Targeted Phenyl-Pyrazolone Derivatives with Antioxidant Properties

et al. 2023

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Orally-active anticancer small molecules targeting the PD-1/PD-L1 immune checkpoint are actively searched. Phenyl-pyrazolone derivatives with a high affinity for PD-L1 have been designed and characterized. In addition, the phenyl-pyrazolone unit acts as a scavenger of oxygen free radicals, providing antioxidant effects. The mechanism is known for the drug edaravone (1) which is also an aldehyde-reactive molecule. The present study reports the synthesis and functional characterization of new molecules (2–5) with an improved anti-PD-L1 activity. The leading fluorinated molecule 5 emerges as a potent checkpoint inhibitor, avidly binding to PD-L1, inducing its dimerization, blocking PD-1/PD-L1 signaling mediated by phosphatase SHP-2 and reactivating the proliferation of CTLL-2 cells in the presence of PD-L1. In parallel, the compound maintains a significant antioxidant activity, characterized using electron paramagnetic resonance (EPR)-based free radical scavenging assays with the probes DPPH and DMPO. The aldehyde reactivity of the molecules was investigated using 4-hydroxynonenal (4-HNE), which is a major lipid peroxidation product. The formation of drug-HNE adducts, monitored by high resolution mass spectrometry (HRMS), was clearly identified and compared for each compound. The study leads to the selection of compound 5 and the dichlorophenyl-pyrazolone unit as a scaffold for the design of small molecule PD-L1 inhibitors endowed with antioxidant properties.

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

Cited by 4 publications

References 52 publications

Microscale Thermophoresis as a Tool to Study Protein Interactions and Their Implication in Human Diseases

Microscale Thermophoresis as a Tool to Study Protein Interactions and Their Implication in Human Diseases

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

Novel PD-L1-Targeted Phenyl-Pyrazolone Derivatives with Antioxidant Properties

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