@misc{10481/64559,
year = {2020},
month = {8},
url = {http://hdl.handle.net/10481/64559},
abstract = {CDK5/p25 kinase plays amajor role in neuronal functions, and is hyperactivated in several
human cancers including glioblastoma and neurodegenerative pathologies such as
Alzheimer’s and Parkinson’s. CDK5 therefore constitutes an attractive pharmacological
target. Since the successful discovery and development of Roscovitine, several
ATP-competitive inhibitors of CDK5 and peptide inhibitors of CDK5/p25 interface have
been developed. However, these compounds suffer limitations associated with their
mechanism of action and nature, thereby calling for alternative targeting strategies. To
date, few allosteric inhibitors have been developed for successful targeting of protein
kinases. Indeed, although this latter class of inhibitors are believed to be more selective
than compounds targeting the active site, they have proven extremely difficult to identify
in high throughput screens. By implementing a fluorescent biosensor that discriminates
against ATP-pocket binding compounds to screen for allosteric inhibitors that target
conformational activation of CDK5, we have identified a novel family of quinazolinones.
Characterization of these hits and several of their derivatives revealed their inhibitory
potential toward CDK5 kinase activity in vitro and to inhibit glioblastoma cell proliferation.
The quinazolinone derivatives described in this study are the first small molecules
reported to target CDK5 at a site other than the ATP pocket, thereby constituting
attractive leads for glioblastoma therapeutics and providing therapeutic perspectives
for neurodegenerative diseases. These compounds offer alternatives to conventional
ATP-competitive inhibitors or peptides targeting CDK5/p25 interface with the potential
of bypassing their limitations.},
organization = {Centre National de la Recherche Scientifique (CNRS)},
organization = {Canceropole Grand Sud Ouest 	
CGSO 2015-E03},
organization = {CBS2 doctoral school of Montpellier University},
organization = {European Union (EU)

PIEF-GA-2013-623151},
publisher = {Frontiers Media SA},
keywords = {CDK5},
keywords = {Kinase},
keywords = {Conformational biosensor},
keywords = {Quinazoline},
keywords = {Small molecule inhibitor},
keywords = {Fluorescence-based screening},
title = {Identification of Quinazolinone Analogs Targeting CDK5 Kinase Activity and Glioblastoma Cell Proliferation},
doi = {10.3389/fchem.2020.00691},
author = {Peyressatre, Marion and González Vera, Juan Antonio},
}