Descrizione del progetto
Una ricerca per rendere i tumori solidi in uno stato non-così-solido
Il trattamento del cancro ha fatto passi da gigante in generale, ma mancano ancora trattamenti efficaci per i tumori solidi. L’oncoproteina MYC è implicata nella comparsa e nel mantenimento dei tumori solidi, ma fino a poco tempo fa i ricercatori credevano che la proteina fosse resistente ai farmaci. Il legame di questo oncogene all’Aurora chinasi A (AurkA) lo protegge dalla decomposizione proteasomica, ma poco si sa su questo processo. Il progetto CSI AurkA-MYC, finanziato dall’UE, mira a comprendere l’interazione AurkA-MYC a livello molecolare. L’obiettivo dei ricercatori è quello di determinare potenziali induttori di cambiamento conformazionale (CSI, Conformational Shift Inducers) in grado di bloccare il legame AurkA-MYC per agevolare la decomposizione del MYC e il trattamento del tumore solido, migliorando i risultati dei pazienti.
Obiettivo
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.
Campo scientifico
Programma(i)
Argomento(i)
Meccanismo di finanziamento
MSCA-IF-EF-ST - Standard EFCoordinatore
72074 Tuebingen
Germania