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

Periodic Reporting for period 1 - CSI AurkA-MYC (Conformational Shift Inducers (CSI): An atomistic level investigation of Aurora kinase A (AurkA)–MYC interaction and its distortion by CSI compounds)

Reporting period: 2019-06-01 to 2021-05-31

In recent years, remarkable progress in cancer research and treatment have been observed, and with the most tumours ever-increasing survival rates are constantly witnessed. Simultaneously, however, little progress is observed in the treatment of some specific solid tumours, such as hepatocellular carcinoma (HCC). Moreover, it has been estimated that by 2035 cancer may even be the leading cause of death in the EU. Therefore, novel therapy options are needed especially for these cancers that are lacking efficient treatment options.

One potential treatment option for a sub-type of HCC is to target MYC protein. Unfortunately, direct MYC targeting appears infeasible due to its highly flexible nature. However, indirect MYC targeting via a protein kinase called Aurora kinase A (AurkA) might be a viable option. There already exist AurkA targeting traditional kinase inhibitors, but their extensive inhibition of the kinase’s enzyme activity may result to on-target toxicity that most often is seen as hematotoxic responses, which limits their usability.

In this action, we investigated so-called conformational shift inducing inhibitors, which disrupt the AurkA–MYC interaction but would have more limited kinase inhibition, potentially offering a suitable therapeutic usage without the side-effects of the potent kinase inhibitors. As MYC (and AurkA) is extremely flexible protein, the objective of the action was to obtain structural understanding of the interplay of these proteins and the binding mode of our conformational shift inducing compounds using computational tools, mainly by long-timescale molecular dynamics simulations. This information would facilitate compound design of the conformational shift inducers, and potentially lead to novel therapy options.
Extensive all-atom molecular dynamics simulations were conducted in the action, including investigations on different protein–protein interactions with and without different small molecule compounds. These simulations aided in understanding how these conformational shift inducers bind to AurkA and suggested the key elements in particular protein–protein interactions that revealed the most important requirements for the small molecule compounds. This information was used in the compound design, guiding the decisions which compounds were selected to be synthesized. Overall, we achieved in highly efficient new conformational shift inducers and have filed a patent application related to this compound series.
Further results of the action will be reported in their course. The results of the action could facilitate further drug development efforts also in other suitable targets, for which indirect targeting could be an option.
Extensive molecular dynamics simulations were conducted in this action.