Project description
Research to render solid tumours to a not-so-solid state
Cancer treatment has advanced in leaps and bounds in general but effective treatments for solid tumours are lacking. The oncoprotein MYC is implicated in the emergence and maintenance of solid tumours but until recently researchers believed the protein was resistant to drugs. The binding of this oncogene to Aurora kinase A (AurkA) protects it from proteasomal degradation but little is known about this process. The EU-funded CSI AurkA-MYC project aims to understand the AurkA-MYC interaction on the molecular level. Their goal is to determine potential conformational shift inducers (CSIs) that can block AurkA-MYC binding to facilitate MYC degradation and solid tumour treatment for better patient outcomes.
Objective
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.
Fields of science
Programme(s)
Funding Scheme
MSCA-IF-EF-ST - Standard EFCoordinator
72074 Tuebingen
Germany