A new approach can help identify high-speed anti-cancer drugs

The enzymes in human cells called histone deacetylases, or HDACs, are targets for a handful of anticancer drugs because of their ability to influence gene expression. Now, researchers from the University of Copenhagen have developed a new way to study how these enzymes work at the molecular level. This new approach can also help identify candidates for anti-cancer drugs at a very high rate.

All the cells in the human body share the same genes. But how our genes are expressed determines whether a cell is going to be a brain cell or a liver cell. In addition, changes in gene expression often play an important role in the development of diseases.

One mechanism that contributes to the changes in gene expression is the interaction between the proteins called histones and enzymes called HDACs. These enzymes help cell division and development, which is why they are targets for anti-cancer treatment: When you block the enzymes, the cancer cells stop from separating and growing longer.

Despite being targets for clinically agreed drugs, researchers do not know all the details of how they work in the cell. Now, researchers from the University of Copenhagen have developed a method that will help change that.

We have revealed details about how these enzymes interact with proteins around our DNA, and our method provides a new way to quickly identify anti-cancer drugs. . In the study, we show that the method works: We synthesized a peptide that affected just the right parts of living human cells, using the same target as today’s anti-cancer treatment practices . “

Carlos Moreno-Yruela, Postdoc, Department of Drug Design and Pharmacology, University of Copenhagen

Peptide effect was unchanged

HDACs are a group of eleven different enzymes, which means that targeting them all at the same time with non-selective medication can affect many essential processes in the body. This may also explain some of the side effects in the clinically approved HDAC anti-cancer treatment.

“Our detailed view of the interaction of the enzymes obtained with the new method gives hope for the development of more specialized HDAC inhibitors with potential as drug candidates. This could be good for the development of more sophisticated compounds. for cancer treatment with fewer side effects, “says Christian Professor Adam Olsen.

In the study, the researchers used the new method to identify peptides, which they converted into larger amounts and which were controlled by human cells. The results were exactly as expected: The expected HDACs were also blocked in live cells.

“It surprised us to see such an obvious effect of an undeveloped peptide in cells. Typically, one would have to introduce a number of modifications to maximize its properties. But the effect was quite strong. at this, an almost entirely natural, peptide, which emphasizes the potential of our products, “says Christian Adam Olsen.

The researchers now hope to use the method to identify promising drug candidates who could advance to preclinical trials.