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)
Berichtszeitraum: 2019-06-01 bis 2021-05-31
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.