A new way to fight harmful proteins in tumor cells

A new active substance attacks a key protein in tumor cells, leading to complete degradation. In cellular experiments, cancer cells lost their protection and died. The active substance was developed by researchers at the Martin Luther University Halle-Wittenberg (MLU) and the University Medical Center Mainz. Other substances generally attempt to inhibit the activity of the checkpoint kinase-1 (CHK1) protein. However, if the protein is completely degraded, a chain reaction is triggered, leading to the destruction of other tumor proteins. Thus, the cancer cells are weakened even more.

The new study was published in Angewandte Chemie International Edition.

Usually, CHK1 is a vital protein for the human body. If errors occur during cell division and the genetic material is damaged, the protein stops the process so the cell can repair it before continuing. However, the protein does not distinguish between normal cells and tumor cells: it protects them in the same way.

Professor Wolfgang Sippl from the Institute of Pharmacy at MLU investigated ways to specifically target and destroy proteins such as CHK1 in tumor cells.

“The general idea is quite simple: if you disrupt the activity of CHK1, cancer cells can no longer repair themselves. This is why many substances try to inhibit the protein. I study so-called PROTAC molecules, which can lead to the breakdown of certain proteins by the body itself,” explains Sippl.

According to the researcher, PROTAC technology has produced promising clinical candidates for the treatment of tumors in recent years.

Sippl, who joined forces with the team of Professor Oliver Krämer from the Institute of Toxicology at the University Medical Center Mainz, was the first to develop a PROTAC molecule called MA203, which binds specifically to the tumor protein CHK1. It ensures that the protein is recognized by the cell’s own degradation mechanism, the proteasome, and is thus broken down into harmless components.

“Chemotherapy drugs are designed to damage the genetic material of cancer cells to prevent them from multiplying. Cellular experiments showed that our molecule, in combination with the drugs, led to increased cell death in solid tumor and leukemia cells,” explains Sippl. Investigations also revealed that MA203 leaves several healthy cell types unchanged.

The researchers also observed a sort of domino effect: Once the CHK1 protein was eliminated in tumor cells, other key proteins that tumors need to replicate and repair their genetic material also began to degrade.

“Our study provides new insights into the role of CHK1 and demonstrates the potential of PROTACs to specifically eliminate key tumor regulatory factors,” says Sippl.

The Halle and Mainz researchers plan further investigations to evaluate the clinical potential of CHK1-targeted PROTACs.

So far, trials have only been conducted on cell cultures and many studies are still needed before MA203 can become a full-fledged drug. This would include large-scale clinical trials on humans.