1,5-Disubstituted tetrazoles as PD-1/PD-L1 antagonists

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61989592%3A15110%2F24%3A73624945" target="_blank" >RIV/61989592:15110/24:73624945 - isvavai.cz</a>

Alternative codes found

RIV/61989592:15640/24:73624945

Result on the web

<a href="https://pubs.rsc.org/en/content/articlelanding/2024/md/d3md00746d" target="_blank" >https://pubs.rsc.org/en/content/articlelanding/2024/md/d3md00746d</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1039/d3md00746d" target="_blank" >10.1039/d3md00746d</a>

Result language

angličtina

Original language name

1,5-Disubstituted tetrazoles as PD-1/PD-L1 antagonists

Original language description

The progress in cancer survival and treatment has witnessed a remarkable transformation through the innovative approach of targeting the inhibitory immune checkpoint protein PD-1/PD-L1 complex by mAbs, e.g. pembrolizumab (Keytruda). While generating 17.2 billion U.S. dollars in revenue in 2021, the true significance of these developments lies in their ability to enhance cancer patient outcomes. Despite the proven efficacy of mAbs in inhibiting the PD-1/PD-L1 signaling pathways, they face significant challenges, including limited response rates, high production costs, missing oral bioavailability, and extended half-lives that can lead to immune-related adverse effects. A promising alternative approach involves the use of small molecules acting as PD-1/PD-L1 antagonists to stimulate PD-L1 dimerization. However, the precise mechanisms of action of these molecules remain partially understood, posing challenges to their development. In this context, our research focuses on the creation of a novel scaffold based on the Ugi tetrazole four-component reaction (UT-4CR) to develop low-molecular-weight inhibitors of PD-L1. Employing structure-based methods, we synthesized a library of small compounds using biphenyl vinyl isocyanide, leading to the discovery of a structure-activity relationship among 1,5-disubstituted tetrazole-based inhibitors. Supported by a cocrystal structure with PD-L1, these inhibitors underwent biophysical testing, including HTRF and protein NMR experiments, resulting in the identification of potent candidates with sub-micromolar PD-L1 affinities. This finding opens opportunities to the further development of a new class of PD-L1 antagonists, holding promise for improved cancer immunotherapy strategies.

Czech name

—

Czech description

—

Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

10401 - Organic chemistry

Project

—

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2024

Confidentiality

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

Name of the periodical

RSC MEDICINAL CHEMISTRY

ISSN

2632-8682

e-ISSN

2632-8682

Volume of the periodical

15

Issue of the periodical within the volume

4

Country of publishing house

GB - UNITED KINGDOM

Number of pages

6

Pages from-to

1210-1215

UT code for WoS article

001184710300001

EID of the result in the Scopus database

2-s2.0-85187997935