The enzyme dihydroorotate dehydrogenase (DHODH) is one the hottest malaria drug targets under investigation today. The University of Texas Southwestern’s project to discover and develop targeted inhibitors with the ability to hit this target and stop the parasite in its tracks was awarded MMV’s 2010 Project of the Year in recognition of its impressive progress to rapidly bring these inhibitors towards clinical testing. Dr Meg Phillips speaks about the project.
1. You had been working on DHODH since 2002, what made you decide to work with MMV in 2006?
In 2006, MMV was getting the reputation for being the people to work with if you had an interesting compound for malaria. As academics, we knew we couldn’t go all the way alone – we needed the help of an organization that had the full antimalarial drug pipeline and so the ability to take a project all the way from discovery, through development to delivery. MMV has always been very transparent in the whole application process and so we felt that since we had an interesting project we stood a fair chance.
2. What did you gain?
To be honest, when we came into this we really didn’t realise how much we were going to gain by being involved with MMV. What has been absolutely fantastic is that we have had access to many great advisers – starting with the Project Directors, Ian Bathurst and Jeremy Burrows. But also as the project has progressed we have received input, as and when needed, from advisers with different expertise. It really has been like working with a virtual drug company.
Through our collaboration with MMV we also came to work with GSK and Genzyme, who were also working on DHODH projects with MMV. MMV was the catalyst – building ties, fostering interactions and really keeping people in line in the interest of promoting drug discovery.
3. What has been the secret to the success of this project?
Success depends on the pooled knowledge of the team and their ability to work through problems to keep the project moving forward. I have a fantastic team and they have worked really hard. But we have been flexible as well; the core team has been augmented as needed.
In the broader context of malaria R&D and feeding the drug pipeline, I think it’s really key that academics continue to work on new targets and understand their biology. MMV is open to working with both academic groups and industry partners and that’s really important as they get different value from each. That’s MMV’s strength – both types of teams are in their portfolio.
Core DHODH Team:
Prof Meg Phillips, University of Texas Southwestern Medical Centre and project leader, responsible for enzymology and structural biology.
Prof. Pradip Rathod, University Washington, responsible for chemistry and parasitology.
Prof. Susan Charman, Monash University, responsible for pharmacokinetics, drug metabolism and physicochemistry.
Significant input from the team at GSK Tres Cantos for medicinal chemistry (Jose Coteron) and in vivo efficacy; and information sharing with Genzyme (Jeff Klinger).
MMV advisors: Ian Bathurst, Jeremy Burrows and several other scientific advisors.
NIH: John Rogers program officer