CSI AurKa-MYC

Conformational Shift Inducers (CSI): An atomistic level investigation of Aurora kinase A (AurkA)–MYC interaction and its distortion by CSI compounds

01/06/2019 to 31/05/2021

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.