Identification of Quinazolinone Analogs Targeting CDK5 Kinase Activity and Glioblastoma Cell Proliferation
MetadataShow full item record
Frontiers Media SA
CDK5KinaseConformational biosensorQuinazolineSmall molecule inhibitorFluorescence-based screening
Peyressatre M, Arama DP, Laure A, González-Vera JA, Pellerano M, Masurier N, Lisowski V and Morris MC (2020) Identification of Quinazolinone Analogs Targeting CDK5 Kinase Activity and Glioblastoma Cell Proliferation. Front. Chem. 8:691.[ doi: 10.3389/fchem.2020.00691]
SponsorshipCentre National de la Recherche Scientifique (CNRS); Canceropole Grand Sud Ouest CGSO 2015-E03; CBS2 doctoral school of Montpellier University; European Union (EU) PIEF-GA-2013-623151
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.