Hit-to-lead development of CaMKII-HDAC4 inhibitory compounds to treat heart failure (project 1: Identification of potent hits)


Funded period

2019 – 2021

Granted budget

€ 553,635

Indication

heart failure

Therapeutic Principle

Drug

Principal Investigator

Johannes Backs (University Hospital Heidelberg)

The two proteins calcium/calmodulin-dependent protein kinase II (CaMKII) and histone deacetylase 4 (HDAC4) are formed in the heart. These play essential roles in maintaining the heart's function, but also in the development of diseases.

When the heart becomes diseased, these two proteins bind together. When the binding was inhibited in mice by genetic intervention, the team observed a protective effect against heart failure. In a first high-throughput screening method, which allows the testing of large amounts of chemical compounds, the scientists found inhibitors that prevent the two proteins from binding together. Furthermore, they were also able to demonstrate this inhibition in cells and observe functional effects. These results suggest that the inhibition of the interaction of CaMKII and HDAC4 is a promising therapeutic target. Together with experts from the Lead Discovery Center in Dortmund, the project group would like to identify more targets for these inhibitors in this project with the help of a second high-throughput search procedure. Promising candidates from this and earlier investigations will then be characterised using a cascade of different functional analyses to determine whether they are suitable for further drug development.


Results

As a result of the project, Heidelberg University Hospital has entered into further cooperation with Lead Discovery Center GmbH (LDC) and the company Novo Nordisk to further develop the compounds. (press release: University Hospital Heidelberg cooperates in the field of cardiology with LDC and Novo Nordisk, 23.3.2021)