JCJC - Jeunes chercheuses et jeunes chercheurs

conception et Synthèse d'inhibiteurs sélectifs des KInases PIm – SKIPI

Submission summary

Pim kinases (Pim-1, 2 and 3) belong to a serine/threonine kinase family which plays important roles in regulating many biological processes linked to cancer disease, including cell survival, cell cycle progress alteration and transcription regulation. Pim kinases are subject to a special interest and it is now established that these kinases are relevant targets to design new anti-tumor agents. A few Pim kinase inhibitors have been described in the literature and, to our knowledge, only three were described as selective of the Pim-1 kinase: quercetagetin, a flavonoid with moderate activity and two organometallic ruthenium complexes of high inhibitory potencies. The coordination sphere of ruthenium, which is a chirality center, is placed inside the ribose pocket of the ATP-binding site of Pim-1 or GSK-3alpha kinases. Indeed, S-complexes were described as selective inhibitors of the Pim-1 kinase. R-enantiomers selectively inhibited GSK-3alpha kinase with high inhibitory activities. Theses examples showed that the selectivity of a kinase inhibitor may depend on the moiety sitting in the ribose pocket. Therefore, in order to optimize both enzymatic affinity and selectivity, the aim of this project is to design and synthesize new Pim kinase inhibitors combining the following structural features: - A heterocyclic aromatic moiety, mimic of the adenine of ATP (this approach is common to all ATP-competitive kinase inhibitors). - Relevant substituents for a high selectivity. - A moiety to anchor the ligand within the ribose pocket of the ATP-binding site. These researches consist on an organic synthesis work, which will use all needed methods to allow the preparation and the characterization of target molecules. Moreover, molecular modelling will be a major asset to define the best Pim kinase inhibitors.

Project coordination

Fabrice ANIZON (Université)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

Help of the ANR 186,492 euros
Beginning and duration of the scientific project: - 48 Months

Useful links

Explorez notre base de projets financés

 

 

ANR makes available its datasets on funded projects, click here to find more.

Sign up for the latest news:
Subscribe to our newsletter