Novel Antimalarial Drugs Through Epigenetics: Full Interview with Dr Matt Fuchter

Malaria is one of the world's largest public health problems and treatments for the disease still leave a lot to be desired. Dr Matthew Fuchter and his team from Imperial College London, have taken a novel approach to malaria treatment, focusing on the importance of epigenetic mechanisms in the malaria parasite. In this exclusive podcast, hear about the development of this new potential treatment.

Pharma IQ: Matt, it's a pleasure to have you here.

M Fuchter: It's a pleasure to be here.

Pharma IQ: Matt, what are histone lysine methyltransferases and why are they important in the differentiation, development and proliferation of P falciparum?

M Fuchter: The histone lysine methyltransferase are a class of enzymes, and these enzymes catalyse the transfer of the methyl group onto lysine amino acids of histone proteins. And the histones are proteins that make up chromatin, so your genetic material. So, within chromatin, DNA is wrapped around the outside of an octamer of histone proteins, and then these histones are subject to modifications such as methylation. Now, when methylated, that has functional consequences on transcription, and so these are really proteins involved in regulating gene expression in a general process called epigenetics. These are proteins that are present in mammalian systems, but they're also present in Plasmodium falciparum, one of the causative agents of human malaria. Indeed, Plasmodium falciparum relies on these proteins to help regulate its gene transcription pathway. So it's really this role that we're interested in; how it uses this protein to basically regulate when and where to transcribe various sets of genes.

Pharma IQ:Why are histone lysine methyltransferases a novel target for antimalarial drug development?

M Fuchter:Really I would say, broadly speaking, there's been a lot of interest in targeting epigenetic processes in disease. This is a growing area, and certainly one of the biggest growth areas in targeting these general, fundamentally important, biological pathways in cancer. In malaria, however, they're far less well studied from a drug discovery point of view. And, indeed, I guess target based drug discovery in malaria, where you pick a molecular target and you optimise a drug towards that target, is often less well studied or less appreciated versus, I guess, phenotypic drug discovery, where you're just screening for compounds that kill the parasite, where the mechanism of action is unknown.

So we decided to take a target approach to target these particular epigenetic enzymes in malaria because we were working with a Professor Artur Scherf at the Pasteur Institute, who's really one of the biological experts of these targets in malaria, and we wanted to develop the first small molecules to interfere with these targets, and therefore observe the effects they have on the Plasmodium parasite.

Pharma IQ:How do your inhibitors, BIX-01294 and TM2-115, work? What is the molecular basis of their rapid induction of parasite death?

M Fuchter:What we had done is BIX-01294 was a known histone lysine methaltransferase inhibitor in the literature, where it had been reported to inhibit a mammalian histone lysine methaltransferase. Now, what we did is we synthesised a chemical library based around this scaffold, and initially we just screened these compounds to look for effects on the parasites. What we saw is, for certain members of this library, particularly BIX-01294 and our other closely related derivative, we saw a rapid induced parasite death in a staged unspecific way; i.e. if you look at the blood stage cycle of the Plasmodium parasite, these drugs kill the parasite regardless of what stage of development that parasite is in, which is a very exciting discovery. What we're starting to do now is trying to get more evidence that the effects we see are due to targeting of the histone lysine methyltransferases. We have evidence that you see a decrease in the methylation marks of the histones that you would expect if you were inhibiting this target, but our plan going forward is to get much more rigorous study to show the effects that we're having on these targets.

But, crudely speaking, what we expect is that our inhibitors work by inhibiting Plasmodium histone lysine methyltransferases. As I said, these are critical targets for Plasmodium transcription; therefore, we're basically inhibiting the ability of the parasite to manage its own gene transcription or programme.

Pharma IQ:How well does the compound work in other Plasmodium species and in in vivo studies?

M Fuchter:We're only really starting to look in other Plasmodium species, so most of our study was on Plasmodium falciparum, which is one of the causative agents of human malaria, and really the most deadly. It causes a vast majority of the malarial deaths. We were focused on this because of the experience we had of epigenetic pathways in this particular Plasmodium parasite, but, moving forward, we're starting to look at other species, and particularly the role that epigenetics could have in other species. So an ongoing activity for us is, for example, studying the dormant stages of Plasmodium vivax. This has a dormant stage in the liver that is responsible for the recurrence of malaria after you've apparently been cured. So a year down the line you develop malaria again through the regeneration of these dormant parasites, and this is a real problem that can't be tackled with current antimalarial drugs. So we're looking at the ability of our compounds, through targeting epigenetic pathways, to basically manipulate this dormant phase of Plasmodium vivax.

In terms of in vivo studies, in our initial studies we did a single experiment in vivo and observed dramatic anti-parasitic effects in vivo, when treated with just a single dose of the compound. This wasn't a complete cure. We didn't see complete destruction of the parasitic material in vivo, but we did see a massive reduction and longer term survival from just a single dose. So now we're starting to more thoroughly explore the in vivo properties of all our compounds, both in terms of their pharmacokinetics and, obviously, in terms of their efficacy in models.

Pharma IQ:You touched on this briefly earlier, but what chemical tools did you use to first identify and develop these compounds?

M Fuchter:Our inspiration came from work targeting human histone lysine methyltransferases. This is a big area of research, and certainly one for my research group. And we really just drew inspiration from a known inhibitor. This inhibitor was identified originally by Boehringer in a high throughput screen. They didn't progress this molecule and so it's been published in the literature for some time, and we used this as inspiration to, as I say, modify this compound synthetically and build a focused library around this core to use as an entry point for potential anti-malarial compounds. And as I say, it was through generating this synthetic library around this scaffold that we identified the potent anti-malarial activity of these small molecules.

Pharma IQ:So it was identified through a screen. How useful are traditional screening method and chemical tools when developing small molecule candidates for epigenetic targets?

M Fuchter:What we chose to do in malaria - these proteins that we're targeting are really quite challenging to handle and to validate in a cell free environment - so we really focused on relatively traditional anti-proliferative assays of the parasite in culture, and did a number of follow up studies. In terms of monitoring the effects on histone methylation, we used traditional immunogenic effects, so things like western blotting and so on. Moving forward, we'll be taking a number of other approaches to develop more on-target focused assays, and also potentially using really chemical biological techniques. For example, making reactive small molecule inhibitors that we can pull down and look to the targets that they are bound to, and further characterise and validate the fact that we're on target with the histone lysine methyltransferases that way.

Pharma IQ:When do you envisage BIX-01294 beginning clinical development?

M Fuchter:That somewhat depends on the possibilities for progression moving forward. We've already had initial discussions with the Medicines for Malaria Venture, and they've assisted us in getting some other preliminary data in terms of initial pharmacokinetic data and some other standard parameters that you would want to see for an early stage anti-malarial compound, to help compare with the pipeline of other potential anti-malarial drugs that are out there. What we hope to do is further engage with organisations such as the Medicines for Malaria Venture, to secure more funding to push this approach forward, and, hopefully, optimise these compounds through iterative medicinal chemistry and in-depth molecular biology, to hopefully optimise these into a clinical candidate. That process will somewhat depend on how successful we are in that endeavour, but certainly I would hope in the time scale of three to five years, we could get towards something into the clinics. But, as I say, it will be somewhat dependent on what happens in the meantime.

Pharma IQ: You said there about the Medicines for Malaria Venture expressing interest. Why do you think this particular trial is generating interest from organisations such as Medicines for Malaria and the Bill & Melinda Gates Foundation?

M Fuchter:The Bill & Melinda Gates Foundation actually funded our preliminary study. They're one of the main funders of our preliminary studies in this area through their Grand Challenges Explorations. And I think why the Medicines for Malaria Venture or organisations such as MMV are interested in our approach is, as I say, I think targeting these particular targets and using them to target epigenetic processes in the parasite in general, is potentially a rather novel approach. Now, in terms of just general cell kill effects, we would just have to see how our compounds stack up against other experimental anti-malarial therapeutic agents in development. That said, since these early stage hits, we see very exciting effects, rapid kill effects, very potent kill effects; and, as I say, stage unspecific effects, which all position us well in that general parasite kill effect for our compounds.

But I think why MMV are also interested in our approach is, potentially, through targeting epigenetic processes in the parasite, we could tackle other areas that are more challenging to tackle currently. For example, I mentioned the dormancy in Plasmodium vivax. Assuming this dormancy is regulated in part by epigenetic processes, then this potentially is a very good way in targeting those. So I think that's another reason MMV may well be interested in what we're doing, because we have good potential to target other stages of the parasite, other species of the Plasmodium that are very tough to tackle via conventional anti-malarial drugs.

Pharma IQ:Thank you very much for sharing your insights and your time with us today. We look forward to hearing more from you at the Epigenetics event. 

M Fuchter:No problem at all. Thank you.


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