The novel PfPI4K inhibitor, UCT943, was selected as a promising new preclinical drug candidate by MMV’s independent Expert Scientific Advisory Committee (ESAC) in 2016. The compound is being developed in partnership with scientists at the University of Cape Town (UCT)’s Drug Discovery and Development Centre, H3D, in South Africa, as a back-up1 to MMV048. From the same chemical family as MMV048, UCT943 has shown impressive potency and solubility in the preclinical setting.
Importantly, it is active against both P. falciparum and P. vivax – across all stages of the parasite lifecycle – and has the potential to be used for chemoprotection and to block transmission of the parasite from person to person. Given the need for new compounds for treatment as well as prophylaxis, there may also be an opportunity to take both compounds forward.
Dr Tanya Paquet, project lead at UCT, tells us how the two compounds compare and talks about the next steps for UCT943.
1. As UCT943 and MMV048 are from the same family, how are they similar and how do they differ?
Both compounds inhibit the intracellular development of the malaria parasite at each stage of its lifecycle, by targeting the same key enzyme. However, small differences in the molecular structure of UCT943 increase its potency and significantly improve its solubility compared with MMV048. This has important implications for drug development, since a molecule with high solubility is less likely to require a complex formulation and can be administered at a lower dose without compromising its efficacy. Such potential benefits will be evaluated against the emerging data for MMV048.
2. What are the next steps in the development of UCT943?
The aim is to complete all preclinical safety and toxicity assessments by year end 2017. At that point, the team, led by the translational medicine team at MMV of which we are part, will review all the available data and decide whether to progress the compound to first-in-human studies.
3. What has it been like to work with MMV on this project?
Quite incredible. Before we started out on this journey, we were a group of university academics who knew very little about malaria or the drug discovery process. Our team back then consisted of only four chemists! Because of this, we had no choice but to outsource a lot of our work. Since partnering with MMV, however, we have grown into a team of around 50 interdisciplinary scientists, and most of our research is now done in-house.
Throughout this process, we’ve had the opportunity to learn from experts in the field and work with inspiring and motivational project directors. Their support has been invaluable and the overall experience has been really beneficial for us. We hope the strong collaboration between UCT and MMV will continue to grow over the coming years.
- A back-up compound is a close analog of the original compound that is structurally related and could replace it, if necessary.