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dc.contributor.authorPeyressatre, Marion
dc.contributor.authorGonzález Vera, Juan Antonio
dc.identifier.citationPeyressatre 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]es_ES
dc.description.abstractCDK5/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.es_ES
dc.description.sponsorshipCentre National de la Recherche Scientifique (CNRS)es_ES
dc.description.sponsorshipCanceropole Grand Sud Ouest CGSO 2015-E03es_ES
dc.description.sponsorshipCBS2 doctoral school of Montpellier Universityes_ES
dc.description.sponsorshipEuropean Union (EU) PIEF-GA-2013-623151es_ES
dc.publisherFrontiers Media SAes_ES
dc.rightsAtribución 3.0 España*
dc.subjectConformational biosensores_ES
dc.subjectSmall molecule inhibitores_ES
dc.subjectFluorescence-based screeninges_ES
dc.titleIdentification of Quinazolinone Analogs Targeting CDK5 Kinase Activity and Glioblastoma Cell Proliferationes_ES

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Atribución 3.0 España
Except where otherwise noted, this item's license is described as Atribución 3.0 España