Protein homodimer sequestration with small molecules: Focus on PD-L1

Bailly, Christian; Vergoten, Gerard

Document type :

Article dans une revue scientifique

DOI :

10.1016/j.bcp.2020.113821

Permalink :

http://hdl.handle.net/20.500.12210/33800

Title :

Protein homodimer sequestration with small molecules: Focus on PD-L1

Author(s) :

Bailly, Christian [Auteur]
Vergoten, Gerard [Auteur]

Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576
Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 [UGSF]

Journal title :

Biochemical Pharmacology

Volume number :

174

Pages :

113821

Publisher :

Elsevier BV

Publication date :

2020-04

ISSN :

0006-2952

English keyword(s) :

Cancer
Immunotherapy
PD-L1
Max
Protein dimer

HAL domain(s) :

Sciences du Vivant [q-bio]
Chimie/Chimie théorique et/ou physique

English abstract : [en]

Monoclonal antibodies targeting the PD-1/PD-L1 immune checkpoint have emerged as efficient cancer biotherapeutics. In parallel, small molecules targeting PD-L1 are actively searched to offer novel therapeutic opportunities ...
Show more >Monoclonal antibodies targeting the PD-1/PD-L1 immune checkpoint have emerged as efficient cancer biotherapeutics. In parallel, small molecules targeting PD-L1 are actively searched to offer novel therapeutic opportunities and to reduce treatment costs. Thus far, all PD-L1 small molecule inhibitors identified present the unique property to induce and to stabilize the formation of PD-L1 protein homodimers. PD-L1 itself can form heterodimers with B7-1 (CD80) but it is essentially monomeric in solution, although the homolog viral protein vOX2 is known to dimerize. Drug-induced sequestration of PD-L1 homodimers prevents binding of PD-L1 to PD-1, thus blocking the downstream signaling. We have analyzed this phenomenon of drug-induced protein dimerization to show that PD-L1 is not an isolated case. Several examples of drug-mediated protein homodimer stabilization are presented here. In particular, a similar phenomenon has been observed with small molecules, such as NSC13728 and KI-MS2-008, which stabilize Max-Max protein homodimers, to block the formation of Myc-Max heterodimers and the ensuing signalization. PD-L1, Max and ten other examples of drug-stabilized protein homodimers point to a general mechanism of protein regulation by small molecules. Nevertheless, the extent and functions of drug-induced PD-L1 homodimers await validation in vivo.Show less >

Language :

Anglais

Peer reviewed article :

Oui

Audience :

Internationale

Popular science :

Non

Administrative institution(s) :

Université de Lille
CNRS

Collections :

Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576

Research team(s) :

Diversité structurale des héparanes sulfates et régulation de la réponse inflammatoire

Submission date :

2020-11-27T12:49:05Z
2020-11-27T13:54:53Z
2020-11-27T13:58:00Z

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Version	Link	Modification date
3	20.500.12210/33800*	2020-11-27T13:57:18Z
2	20.500.12210/33800.2	2020-11-27T13:47:27Z
1	20.500.12210/33800.1	2020-11-27T12:49:05Z

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