Promising way to find new cancer drugs

Date:
January 25, 2021
Source:
University of Copenhagen - The Faculty of Health and Medical
Sciences
Summary:
The enzymes in human cells known as histone deacetylases, or
HDACs, are targets for a handful of anticancer drugs because of
their ability to affect gene expression. Now, researchers have
developed a new method to investigate how these enzymes work on
a molecular level. This new method can also help identify more
precise possible anti-cancer drug candidates at a very high pace.



FULL STORY ==========================================================================
All the cells in the human body share the same genes. But how our genes
are expressed determines whether a cell becomes a brain cell or a liver
cell. In addition, changes in gene expression often play a significant
role in development of diseases.


==========================================================================
One mechanism that contributes to the changes in gene expression is
the interaction between the proteins called histones and enzymes known
as HDACs.

These enzymes help the cell divide and develop, which is the reason why
they serve as targets for anti-cancer medicine: When you inhibit the
enzymes, the cancer cells will stop dividing and growing further.

Despite being targets for clinically approved medicines, 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 shown details of how these enzymes interact with proteins around
our DNA, and our method provides a new means for identifying possible anti-cancer drugs very quickly. 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 anti-cancer medicine uses
today," says Carlos Moreno-Yruela, postdoc at the Department of Drug
Design and Pharmacology.

Unmodified peptide had effect HDACs are a group of eleven different
enzymes, which means that targeting them all at once with a non-selective medicine will result in affecting many essential processes in the
body. This may also explain some of the side effects in the clinically
approved HDAC-inhibiting anti-cancer medicine.

"Our detailed insight into the enzymes' interactions gained with the
new method provide hope for the development of more specific HDAC
inhibitors with potential as drug candidates. This could bode well for
the development of more sophisticated compounds for cancer therapy with
fewer side effects," says Professor Christian Adam Olsen.

In the study, the researchers used the new method for identifying
peptides, which they resynthesized in larger amounts and subjected to
human cells. The results were exactly what they hoped: The expected
HDACs were also inhibited in living cells.

"We were surprised to see such a prominent effect of an unoptimized
peptide in cells. Normally, one would need to introduce a variety of modifications to optimize its properties. But this, almost fully natural, peptide had a really potent effect, which emphasizes the potential of
our findings," says Christian Adam Olsen.

The researchers now hope to use the method for identifying promising
drug candidates which could go on to pre-clinical testing.


========================================================================== Story Source: Materials provided by University_of_Copenhagen_-_The_Faculty_of_Health_and
Medical_Sciences. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Carlos Moreno-Yruela, Michael Baek, Adela-Eugenie Vrsanova, Clemens
Schulte, Hans M. Maric, Christian A. Olsen. Hydroxamic acid-modified
peptide microarrays for profiling isozyme-selective interactions
and inhibition of histone deacetylases. Nature Communications,
2021; 12 (1) DOI: 10.1038/s41467-020-20250-9 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/01/210125144630.htm

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