Description du projet
Une recherche pour faire passer les tumeurs de l‘état solides à un état moins solide
Le traitement du cancer a progressé à pas de géant en général, mais les traitements efficaces contre les tumeurs solides font défaut. L’oncoprotéine MYC est impliquée dans l’émergence et le maintien de tumeurs solides, mais jusqu’à récemment, les chercheurs pensaient que la protéine était résistante aux médicaments. La liaison de cet oncogène à Aurora kinase A (AurkA) le protège de la dégradation protéasomique, mais on sait peu de choses sur ce processus. Le projet CSI AurkA-MYC, financé par l’UE, vise à comprendre l’interaction AurkA-MYC au niveau moléculaire. Son objectif consiste à déterminer les inducteurs potentiels de décalage conformationnel (CSI) pouvant bloquer la liaison AurkA-MYC pour faciliter la dégradation du MYC et le traitement des tumeurs solides pour de meilleurs résultats pour les patients.
Objectif
In recent years, remarkable advances in cancer research and treatment have been made. Still, little progress is observed in the treatment of specific solid tumours, e.g. hepatocellular carcinoma. The oncoprotein MYC is frequently involved in the genesis and maintenance of human solid tumours and therefore represents a highly promising drug target. Unfortunately, as MYC does not withhold any potential binding cavities for druglike small-molecules, it has been long considered as an undruggable protein. Recently, however, a potential way to target this oncogene indirectly via Aurora kinase A (AurkA) was introduced. When bound to MYC, AurkA shields it from proteasomal degradation. Specific AurkA inhibitors that are conformational shift inducers (CSIs) prevent MYC binding to AurkA, finally leading to MYC’s proteasomal degradation. This type of inhibition holds a great promise for indirectly targeting MYC. However, the precise mechanism of AurkA–MYC binding is unknown and it is unclear what the most important characteristics of a CSI compound in preventing this protein–protein interaction are. These uncertainties are currently the limiting step in the compound design process and hinder the ongoing drug development. To this end, this research project aims to characterize and study the AurkA–MYC interaction and CSI compounds’ binding to AurkA by long-timescale all-atom molecular dynamics (MD) simulations. The main objectives of this research are to understand the AurkA–MYC interaction on the molecular level and to provide a mechanistic explanation of why the CSI compounds prevent the MYC binding. As a result, this research will guide the design and development of CSIs and thus may provide therapeutic possibilities for cancers with inadequate treatment options. Finally, this will establish a new way to utilize MD simulations in drug discovery and design that may be transferred to other potential drug targets in future.
Champ scientifique
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Régime de financement
MSCA-IF-EF-ST - Standard EFCoordinateur
72074 Tuebingen
Allemagne