A word with Anton Bennett

Q: Phosphatases as a target class are known to be difficult to address with therapeutic strategies. Can you share an example from your previous work and how your team dealt with the challenges?

A: A few years ago, my team was working on a possible new treatment for Duchenne muscular dystrophy (DMD), a rare genetic disease, by targeting a phosphatase called MKP5. My team and our collaborators screened more than 162,000 molecular compounds and identified one candidate that was binding to a previously undiscovered allosteric site on MKP5. Binding of the inhibitor to this pocket collapsed the MKP5 active site which provided a molecular explanation for how this inhibitor worked. Remarkably, we discovered that this allosteric site is conserved amongst other MKP family members but with each having subtle differences. This suggests that we could apply this strategy to selectively target other MKPs, and served as an excellent starting point for a drug development program that circumvented previous problems with targeting the MKPs.

Q: Even with a promising drug molecule at hand, what other factors need to be considered to lead phosphatase-modulating therapeutics to a wider success?

A: One of the major areas that will be important to address is the issue of specificity. Phosphatases have the unfortunate reputation of being highly promiscuous. This is of course, not the case, but this perception seems to burden the development path with having to meet much higher standards in demonstrating on-target engagement. Therefore, stringent assessment of target specificity needs to be incorporated into the phosphatase development workflow. Success in this area is critical but at the same time can be a pivotal springboard for broadening the therapeutic indications. In my previous example, while we initially tested the compound in muscle cells as a new therapeutic strategy for treating DMD, the implications went well beyond muscular dystrophy. The MKP5 enzyme is broadly implicated in fibrosis, or the buildup of scar tissue. Fibrosis is involved in the end-stage death of many tissues, including liver, lung, and muscle, and thus contributes to nearly one-third of natural deaths worldwide. The success of a MKP5 inhibitor could be highly impactful.

Q: Football or Soccer?

A: I was born in the U.K. and grew-up in London and have followed my favorite team Tottenham Hotspur all my life. So, it will always be football for me. However, now that I have been living in the U.S.A. and my son plays football here, I have softened my opinion and in certain circles I do refer to football as “soccer”. So, a bit of both, in the end.