Descripción del proyecto
Investigación para dejar a los tumores sólidos en un estado no tan sólido
El tratamiento del cáncer ha avanzado a pasos agigantados en general, pero se carece de tratamientos eficaces para los tumores sólidos. La oncoproteína MYC interviene en la aparición y el mantenimiento de los tumores sólidos, pero, hasta hace poco, los investigadores creían que esta proteína era farmacorresistente. La unión de este oncogén con Aurora quinasa A (AurkA) lo protege de la degradación proteasomal, pero se sabe muy poco sobre este proceso. El proyecto financiado con fondos europeos CSI AurkA-MYC se propone comprender la interacción AurkA-MYC a escala molecular. Su objetivo es determinar los posibles inductores de cambios conformacionales (CSI, por sus siglas en inglés) que pueden bloquear la unión AurkA-MYC para facilitar la degradación de MYC y el tratamiento del tumor sólido con el fin de conseguir unos mejores resultados para los pacientes.
Objetivo
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.
Ámbito científico
Programa(s)
Régimen de financiación
MSCA-IF-EF-ST - Standard EFCoordinador
72074 Tuebingen
Alemania