C2-Symmetrical Terphenyl Derivatives as Small Molecule Inhibitors of Programmed Cell Death 1/Programmed Death Ligand 1 Protein–Protein Interaction

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61989592%3A15110%2F24%3A73625305" target="_blank" >RIV/61989592:15110/24:73625305 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/61989592:15640/24:73625305

Výsledek na webu

<a href="https://www.mdpi.com/1420-3049/29/11/2646" target="_blank" >https://www.mdpi.com/1420-3049/29/11/2646</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.3390/molecules29112646" target="_blank" >10.3390/molecules29112646</a>

Jazyk výsledku

angličtina

Název v původním jazyce

C2-Symmetrical Terphenyl Derivatives as Small Molecule Inhibitors of Programmed Cell Death 1/Programmed Death Ligand 1 Protein–Protein Interaction

Popis výsledku v původním jazyce

The PD-1/PD-L1 complex is an immune checkpoint responsible for regulating the natural immune response, but also allows tumors to escape immune surveillance. Inhibition of the PD-1/PD-L1 axis positively contributes to the efficacy of cancer treatment. The only available therapeutics targeting PD-1/PD-L1 are monoclonal antibody-based drugs, which have several limitations. Therefore, small molecule compounds are emerging as an attractive alternative that can potentially overcome the drawbacks of mAb-based therapy. In this article, we present a novel class of small molecule compounds based on the terphenyl scaffold that bind to PD-L1. The general architecture of the presented structures is characterized by axial symmetry and consists of three elements: an m-terphenyl core, an additional aromatic ring, and a solubilizing agent. Using molecular docking, we designed a series of final compounds, which were subsequently synthesized and tested in HTRF assay and NMR binding assay to evaluate their activity. In addition, we performed an in-depth analysis of the mutual arrangement of the phenyl rings of the terphenyl core within the binding pocket of PD-L1 and found several correlations between the plane angle values and the affinity of the compounds towards the protein.

Název v anglickém jazyce

C2-Symmetrical Terphenyl Derivatives as Small Molecule Inhibitors of Programmed Cell Death 1/Programmed Death Ligand 1 Protein–Protein Interaction

Popis výsledku anglicky

The PD-1/PD-L1 complex is an immune checkpoint responsible for regulating the natural immune response, but also allows tumors to escape immune surveillance. Inhibition of the PD-1/PD-L1 axis positively contributes to the efficacy of cancer treatment. The only available therapeutics targeting PD-1/PD-L1 are monoclonal antibody-based drugs, which have several limitations. Therefore, small molecule compounds are emerging as an attractive alternative that can potentially overcome the drawbacks of mAb-based therapy. In this article, we present a novel class of small molecule compounds based on the terphenyl scaffold that bind to PD-L1. The general architecture of the presented structures is characterized by axial symmetry and consists of three elements: an m-terphenyl core, an additional aromatic ring, and a solubilizing agent. Using molecular docking, we designed a series of final compounds, which were subsequently synthesized and tested in HTRF assay and NMR binding assay to evaluate their activity. In addition, we performed an in-depth analysis of the mutual arrangement of the phenyl rings of the terphenyl core within the binding pocket of PD-L1 and found several correlations between the plane angle values and the affinity of the compounds towards the protein.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10401 - Organic chemistry

Projekt

—

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2024

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

MOLECULES

ISSN

1420-3049

e-ISSN

—

Svazek periodika

29

Číslo periodika v rámci svazku

11

Stát vydavatele periodika

CH - Švýcarská konfederace

Počet stran výsledku

25

Strana od-do

nestránkováno

Kód UT WoS článku

001281724500001

EID výsledku v databázi Scopus

2-s2.0-85195897016