Targeted protein degradation: Researchers find new way to combat harmful proteins in tumour cells
Domino effect in the fight against cancer
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A new active substance attacks a key protein in tumour cells, leading to complete degradation. In cell experiments, this caused cancer cells to lose their protection and die. The active substance was developed by researchers at the Martin Luther University Halle-Wittenberg (MLU) and the University Medical Center Mainz. Other substances usually try to inhibit the activity of the protein “checkpoint kinase-1” (CHK1). However, if the protein is completely broken down, a chain reaction is triggered which leads to other tumour proteins being destroyed. Thus, the cancer cells are further weakened. The new study was published in the journal “Angewandte Chemie”.
Usually, CHK1 is a vital protein for the human body. If errors occur during cell division and the genetic material is damaged, the protein halts the process so that the cell can repair it before proceeding. However, the protein does not distinguish between normal cells and tumour cells – it protects them equally.
Professor Wolfgang Sippl from the Institute of Pharmacy at MLU has been studying ways to specifically target and destroy proteins such as CHK1 in tumour cells. “The general idea is rather simple: if you disrupt the activity of CHK1, cancer cells can no longer repair themselves. Therefore, many substances try to inhibit the protein. I am investigating so-called PROTAC molecules, which can lead to certain proteins being broken down by the body itself”, Sippl explains. According to the researcher, PROTAC technology has produced promising clinical candidates for tumour treatment in recent years.
Sippl, who joined forces with Professor Oliver Krämer’s team from the Institute of Toxicology at the University Medical Center Mainz, was the first to develop a PROTAC molecule called MA203, which specifically binds to the tumour protein CHK1. There it ensures that the protein is recognised by the cell’s own degradation machinery, 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. Cell experiments have shown that our molecule, in combination with the drugs, led to increased cell death in solid tumour and leukaemia cells,” says Sippl. The investigations also found that MA203 leaves several types of healthy cells unaffected.
The researchers also observed a kind of domino effect: once the CHK1 protein was eliminated in tumour cells, other key proteins that tumours need to replicate and repair their genetic material also started to degrade. “Our study provides new insights into the role of CHK1 and demonstrates the potential of PROTACs to specifically eliminate key tumour regulation factors,” says Sippl. The researchers from Halle and Mainz are planning further investigations to evaluate the clinical potential of CHK1-targeted PROTACs.
So far, the trials have only been conducted in cell cultures and numerous studies are still needed before MA203 can become a fully-fledged drug. These would include large-scale clinical trials in humans.
The study was supported by the German Research Foundation (DFG), the Brigitte and Dr Konstanze Wegener Foundation, the German Academic Exchange Service, the Walter Schulz Foundation, the José Carreras Leukaemia Foundation and the Alexander von Humboldt Foundation.
Original publication
Ramy Ashry, Mohamed Abdelsalam, Julia Hausen, Christoph Hieber, Yanira Zeyn, Anne‐Christin Sarnow, Matthias Schmidt, Sara Najafi, Ina Oehme, Matthias Bros, Jia‐Xuan Chen, Mario Dejung, Wolfgang Sippl, Oliver H. Krämer; "Identification of a Proteolysis‐Targeting‐Chimera that Addresses Activated Checkpoint Kinase‐1 Reveals its Non‐Catalytic Functions in Tumor Cells"; Angewandte Chemie International Edition, 2025-10-17
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