Scientists in Dundee have made a major discovery that could lead to new cancer treatments with fewer side effects. They have found how some cancer drugs can target specific proteins that are essential for the survival of cancer cells.
The role of protein kinases in cancer
Protein kinases are enzymes that regulate the activity of other proteins by adding phosphate groups to them. They are involved in many cellular processes, such as growth, division, survival, and movement. However, when protein kinases are mutated or overexpressed, they can cause cancer by driving uncontrolled cell proliferation and resistance to cell death.
There are more than 500 different protein kinases in the human genome, and many of them are potential targets for cancer therapy. However, most of the existing drugs that inhibit protein kinases are not very selective, meaning that they can also affect normal cells and cause unwanted side effects. Therefore, there is a need for more specific and effective inhibitors that can target only the cancer-causing kinases.
The discovery of a new mechanism of action
A team of researchers from the University of Dundee, led by Professor Alessio Ciulli, has discovered a new way of targeting protein kinases with drugs that could overcome some of the limitations of the current inhibitors. They have found that some drugs can bind to a region of the kinase that is normally hidden inside the protein, and induce a conformational change that exposes it to the surface. This region, called the activation segment, is crucial for the kinase activity and stability.
By binding to the activation segment, the drugs can disrupt the function of the kinase and trigger its degradation by the cell’s quality control system. This mechanism of action is different from the conventional inhibitors, which usually bind to the active site of the kinase and block its catalytic activity. The researchers have named this new class of drugs “molecular glues”, because they can glue together different parts of the kinase and alter its shape.
The researchers have demonstrated this mechanism of action with two drugs, called BI-2852 and BI-3812, which target a protein kinase called BRD4. BRD4 is a key regulator of gene expression and cell cycle, and it is implicated in several types of cancer, such as leukemia, lymphoma, and lung cancer. The drugs can bind to the activation segment of BRD4 and induce its degradation, leading to reduced cell growth and increased cell death.
The potential implications for cancer treatment
The discovery of this new mechanism of action could have important implications for the development of new cancer treatments with fewer side effects. The researchers believe that this approach could be applied to other protein kinases that have a similar activation segment, and that it could be combined with other strategies to enhance the specificity and efficacy of the drugs.
Professor Ciulli said: “This is a major scientific advance that challenges the dogma of how to target protein kinases with drugs. We have discovered a new way of making these proteins destroy themselves, which could lead to new and better therapies for cancer and other diseases.”
He added: “We are very excited about the potential of this approach, but we are still at an early stage of the research. We need to do more work to understand how this mechanism works in more detail, and to test its applicability to other kinases and other diseases.”
