Behind the Science: Effect of Various Zinc Binding Groups on Inhibition of HDACs

Behind the Science: Effect of Various Zinc Binding Groups on Inhibition of HDACs

Author: Scott Williams

Dr. Scott Williams, Senior Associate Editor for ChemMedChem, talks to Professor Christian A. Olsen (pictured), University of Copenhagen, Denmark, about his article on a series of histone deacetylase (HDAC) inhibitors with zinc binding domains that was published in ChemMedChem.
HDAC inhibitors have shown great promise as anticancer agents and Olsen’s research group is at the forefront of developing subtype-specific HDAC inhibitors.


Your research is in the relatively young and dynamic field of epigenetics, and for this paper, your research group used state-of-the-art biochemical profiling methods to determine the selectivity of a series of compounds toward HDACs.
What was the motivation behind this work?

My laboratory works on several projects related to epigenetics. We are particularly interested in lysine acetylation and more recently other types of acylation as well. The work described in our article in the ChemMedChem Special Issue on epigenetics was actually derived from a project in which we combined cyclotetrapeptide and cyclodepsipeptide structures with a variety of zinc-binding groups. We came to the conclusion that evaluation of the various zinc-binding groups of interest on more simple scaffolds would provide us with a better idea of their individual activities.
This initiated the work described in our paper, and the combination with more elaborate macrocylic chemotypes is still ongoing.


What is the primary significance of your results?

There are two primary findings that surfaced from our profiling:

  1. that the trifluoromethyl ketone zinc-binding group may confer strong binding to all the human HDACs 1–11. This was not highly surprising, but nevertheless, this had not been shown as systematically before.
  2. We showed that silanediol, which has previously been applied as a transition-state mimic in protease inhibitors, can be applied as a zinc-binding group in HDAC inhibitiors.

Finally, we observed some interesting trends in the importance of linker length, upon which we will have to elaborate further.


Roughly how long did it take to conduct the research reported in this paper?

This is difficult to answer, as the story branched out from a larger program in my laboratory. We have been working in this area since I started my independent research group in 2010.


What are the next steps you plan to take in this project?

As already mentioned, we have a strong interest in macrocyclic peptide-based structures, which we will combine with various zinc-binding groups from the published study as well as a few other ones that I cannot disclose at this time.


How did you become interested in pursuing questions in the field of epigenetics?

I adopted a keen interest in this field during my postdoctoral tenure in the laboratory of Professor M. Reza Ghadiri at the Scripps Research Institute in La Jolla, CA, USA.


Is your research group involved in any other projects?

We certainly are. In addition to the already mentioned directions, we are also very interested in discovering novel enzymatic activities related to de-acylation of lysine residues in proteins using chemical tools. We also pursue efforts in the field of new types of foldamers with interesting properties.


What is your longer-term vision for your research career, i.e., are there any new or different research areas you hope to embark on sometime?

At this point, we have really just scratched the surface of all the different areas we are involved in and thus have a lot of work ahead of us. To gain a deeper understanding of the various systems of interest, we will have to develop several new techniques in the laboratory. One of these directions could well be the exciting field of protein synthesis methods enabling site-specific post-translational modification, which can be achieved in several ways today.

More generally, I have thus far been blessed with the ability to work with excellent students and colleagues. I sincerely hope that I will be able to continuously recruit young talents to perform research in my group and to watch them develop into brilliant scientists.

The article they talked about:

Professor Christian A. Olsen was recently awarded the European Federation for Medicinal Chemistry (EFMC) Prize for a Young Medicinal Chemist in Academia, and the results of his research were featured prominently in ChemMedChem’s Special Issue on Epigenetics last March. 


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