Ann Nguyen:

Hello. My name is Ann Nguyen, Senior Associate Conference Producer at Cambridge Healthtech Institute. Today we have a special podcast for the Targeting Histone Methyltransferases and Demethylases meeting, part of the 14th Annual Discovery on Target event, September 20-21 in Boston.

We are very excited to have joining us by phone Professor Chris Schofield, Head of Organic Chemistry in the Chemistry Research Laboratory at the University of Oxford.

Chris, thank you very much for joining us today. Let's get started.

A portion of your research focuses on the discovery of novel histone demethylase inhibitors. How have you seen this space evolve over the past few years? What are some demethylase targets currently being pursued by medicinal chemists?

Christopher Schofield:

Starting off from very small beginnings, it's been fantastic to see pace of progress in the histone demethylase inhibitor field begin. We came to the field from a slightly less field direction in that we working on the fundamental science of oxygen sensing in humans and other animals. We found that one of the oxygen sensors we worked on is related to histone demethylases. In early work we took some of our oxygen sensing inhibitors and tested them against histone demethylases and we showed that they worked against histone demethylases.

Subsequently it's been fantastic to see interest in the field grow to the state where there's now multiple academic and industrial companies working in the field. Most of the current interest concerns targets like cancer. For example the KDM5 enzymes have lot of interest at the moment.

From our own group's perspective we're more generally interested in links between histone modifications and other post-translational modifications related to chromatin biology and physiology. The ideal project for our group has interesting chemistry and the histone demethylases certainly take that box, has clinical relevance. I think at this stage there's definitely a lot of promise there yet, but the extent which they'll be useful as clinically relevant targets in the next decade or so is not clear at this stage.

Finally we like to have a project that's of basic biological importance. That's certainly been the case with the histone demethylases.

Ann Nguyen:

Can you please describe some of the work currently being conducted in your lab toward the discovery of new demethylase inhibitors?

Christopher Schofield:

We're working this project from different perspectives. We started off in the field with classical small molecule inhibitors. That's still an area in which we still have an interest, including by helping and promoting work in both academia and industry. We're also interested in developing new targets to inhibitors for the histone demethylases. We see it as one of the roles of academia to pioneer new fields. We're particularly interested in using those inhibitors to attempt to understand how histone modifications relate to physiology.

Within that regard we're interested in developing inhibitors that don't bind to the active site of a histone demethylase, substrate-competing inhibitors, that's with my colleague Akane Kawamura, and inhibitors that bind to the non-catalytic domains of histone demethylases that, in some cases at least, we now know are as important for function as the actual catalytic domains.

Ann Nguyen:

What challenges have been encountered designing small molecule histone demethylase inhibitors?

Christopher Schofield:

I guess these challenges fall into two categories. The first category is getting selected small molecules for the catalytic domains of histone demethylases. They’re a family of histones demethylases that our group is interested in employ ferrous-ion and … as a co-substrate. These enzymes have been … previously but there's not huge amounts of work on them. Those would be classical medicinal chemistry challenges that history would suggest can be overcome. The major challenge in the field is that we don't understand exactly what the histone demethylases do, both in terms of cellular roles and importantly how those cellular roles connect to physiology. Almost all the histone demethylases have non-catalytic domains that are involved in determining their function. They likely have a myriad of other interactions, many likely transient, that relate to their physiological roles.

From my perspective the biggest challenge will be attempting to predict the physiological effects in animals that small molecule inhibitors of histone demethylases will have.

Ann Nguyen:

We always end our podcasts with an outlook. How do you see this research evolving over the next few years?

Christopher Schofield:

This relates to my previous answer. This is an easy answer. We need to connect the cellular results to what I call real biology, whole animal physiology. I think the potential in the histone modifying field is absolutely enormous for changing animal physiology. The underlying chemistry, I think the available evidence is, is incredibly complicated. I think we have to have a little bit of humility about how little we know about that complexity at this stage, and how little we're likely to know in the course of the next decade or two in terms of predicting what small molecule and other types of modulators on histone demethylases might have.

Ann Nguyen:

With that I think we'll wrap up. Chris, it was a pleasure speaking with you. Thank you for your time and we look forward to the continuation of your work targeting histone demethylases. For those listening, explore the Discovery on Target website, www.discoveryontarget.com, for additional information. Thank you for tuning in and we look forward to seeing you at the conference. Goodbye.