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

Informazioni relative al progetto

CSI AurkA-MYC

ID dell’accordo di sovvenzione: 839230

DOI

10.3030/839230

Progetto chiuso

Data della firma CE 19 Marzo 2019

Data di avvio 1 Giugno 2019

Data di completamento 31 Maggio 2021

Finanziato da

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Costo totale

€ 174 806,40

Contributo UE

€ 174 806,40

Coordinato da

EBERHARD KARLS UNIVERSITAET TUEBINGEN
Germany

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)

Periodo di rendicontazione: 2019-06-01 al 2021-05-31

Sintesi del contesto e degli obiettivi generali del progetto

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.

Lavoro eseguito dall’inizio del progetto fino alla fine del periodo coperto dalla relazione e principali risultati finora ottenuti

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.

Progressi oltre lo stato dell’arte e potenziale impatto previsto (incluso l’impatto socioeconomico e le implicazioni sociali più ampie del progetto fino ad ora)

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.