Titre :

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

Auteur(s) :

Regnault, Romain [Auteur]
Groupe de Recherche sur les formes Injectables et les Technologies Associées - ULR 7365 [GRITA]
Klupsch, Frédérique [Auteur]
Institute for Translational Research in Inflammation - U 1286 [INFINITE]
El-Bouazzati, Hassiba [Auteur]
Miniaturisation pour la Synthèse, l’Analyse et la Protéomique - UAR 3290 [MSAP]
Magnez, Romain [Auteur]
Miniaturisation pour la Synthèse, l’Analyse et la Protéomique - UAR 3290 [MSAP]
Le Biannic, Raphaël [Auteur]
Institute for Translational Research in Inflammation - U 1286 [INFINITE]
Leleu-Chavain, Natascha [Auteur]
Institute for Translational Research in Inflammation - U 1286 [INFINITE]
Ahouari, Hania [Auteur]
Laboratoire Avancé de Spectroscopie pour les Intéractions la Réactivité et l'Environnement - UMR 8516 [LASIRE]
Vezin, Herve [Auteur]
Laboratoire Avancé de Spectroscopie pour les Intéractions la Réactivité et l'Environnement - UMR 8516 [LASIRE]
MILLET, Régis [Auteur]
Lille Inflammation Research International Center - U 995 [LIRIC]
Goossens, Jean-François [Auteur]
Groupe de Recherche sur les formes Injectables et les Technologies Associées - ULR 7365 [GRITA]
Thuru, Xavier [Auteur]
Hétérogénéité, Plasticité et Résistance aux Thérapies des Cancers = Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 [CANTHER]
Bailly, Christian [Auteur]
Hétérogénéité, Plasticité et Résistance aux Thérapies des Cancers = Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 [CANTHER]

Titre de la revue :

Molecules

Pagination :

3491

Éditeur :

MDPI

Date de publication :

2023-04-15

ISSN :

1420-3049

Mot(s)-clé(s) en anglais :

aldehyde reactivity
antioxidant
cancer
immune checkpoint
PD-L1 binding
pyrazolone

Discipline(s) HAL :

Chimie/Chimie théorique et/ou physique

Résumé en anglais : [en]

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 ...
Lire la suite >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.Lire moins >

Langue :

Anglais

Audience :

Internationale

Vulgarisation :

Non

Collections :

• Miniaturisation pour la Synthèse, l'Analyse et la Protéomique (MSAP) - USR 3290

Source :

Harvested from HAL