- Awarded Year2016
- Awarded Amount$483,360
- Development StageLead Identification
- Collaboration PartnersTakeda Pharmaceutical Company Limited, Medicines for Malaria Venture (MMV)
Introduction and Background of the Project
This is a continuation project of 'Antimalarial hits from whole cell screening' invested in 2015.
Malaria, a mosquito-borne parasite, can still infect over 200 million people per year. There were an estimated 438,000 malaria deaths worldwide in 2015 with 78% of global malaria deaths which were estimated to occur in children under 5 years of age (1). Novel classes of antimalarial medicines targeting different parasite stages are urgently needed to provide both effective alternatives when resistance to current therapies will inevitably progress and the ingredients needed to meet the malaria eradication agenda (2).
This project builds on the screening of a Takeda 20,000 compound library against the asexual blood, liver and sexual stages of malaria. The library was made up of high quality, diverse proprietary compounds synthesized/purchased by Takeda. The screening was performed at MMV testing centres in USA (Prof. Winzeler – University of California, San Diego) and in Australia (Prof. Vicky Avery – Griffith Institute for Drug Discovery, Griffith University) against the liver (3), blood asexual (4) and sexual (5) stages of the malaria parasite. The project team is now working on four confirmed chemical hit series inhibiting the asexual blood and the liver stages of the parasite life cycle –including one series directly repurposed from Takeda portfolio–
The objectives for the project are to transform these hits, identified among the high-throughput screening, into Lead series with proven in vivo efficacy at the animal disease models so as to identify before April 2018 at least one compound series that meets the GHIT/MMV criteria for progression to Lead Optimization stage.
During the first phase of the project, frontrunner compounds from the four series selected for hit-to-lead progression will be profiled in the parasite life cycle assays to confirm their Target Candidate Profile (TCP). In parallel, medicinal chemistry will be carried out and analogues will be profiled in parasitology and cytotoxicity assays. The physicochemical properties, stability and ADMET characteristics will also be determined. Then the most promising compounds will be evaluated in rodents PK experiments and in the disease model of human malaria to demonstrate in vivo efficacy. After further optimization of their properties, the goal is to select a couple of lead molecules which will be the basis of a new proposal to GHIT for a Lead Optimization program.
How can your partnership (project) address global health challenges?
In the fight against malaria new medicines are essential weapons. For the parts of the world where the current gold standard artemisinin combination therapies are active, significant improvements can still be made. For example, there is a need for combination medicines allowing single dose regimens that are cheaper, safer and more effective and/or with improved stability under field conditions. In the absence of a highly effective vaccine, new drugs are needed to protect patient populations. Moreover, in the context of the malaria eradication agenda endorsed by the Bill and Melinda Gates Foundation and the WHO, new attributes to malaria medicines are required, such as the ability to block transmission between human and mosquitoes and to kill the dormant liver stages. Unfortunately, the current pipeline not only lacks compounds that meet all of these criteria, but it also has very few compounds with novel mechanisms-of-action that would be useful to combat growing artemisinin resistance. MMV has worked with the wider malaria community to establish Target Candidate Profiles (TCPs) that define the attributes of the next-generation antimalarials needed to not only control but also eradicate the disease (7). This collaborative project between Takeda, MMV and GHIT is focused on delivering compounds that meet at least one of the TCPs, such as i) rapid clearance of blood-stage parasites to relieve disease symptoms quickly, ii) long-acting profile that, in a combination regimen, is capable of providing a total cure and post-treatment prophylaxis, iii) anti-relapse medicine for patients infected with Plasmodium vivax and Plasmodium ovale, iv) transmission blocking medicine targeting the host gametocyte population and preventing infection to the mosquito and v) chemoprotective agent capable of protecting vulnerable populations from reinfection.
What sort of innovation are you bringing in your project?
The series which are currently investigated have been prioritised based on novelty of the chemotype (and, by inference, the mode of action), life-cycle fingerprint (in particular dual asexual blood and liver stage activities) relevant for eradication potential, and the extent to which they fill strategic gaps in the MMV portfolio. Compound series will only be proposed for Lead Optimization if they fulfill the GHIT-MMV criteria (8) and also offer differentiation compared to existing series in the MMV portfolio at the time of the proposal.
Role and Responsibility of Each Partner
The project team consists of medicinal chemistry and biology experts from Takeda and MMV as well as parasitology and DMPK specialists from within the MMV network. Takeda's role is to make scientific advices for the medicinal chemistry plans, the selection of analogues for further studies and the profiling of the hit chemical series with scientists from MMV, Griffith university and Monash University. Takeda is also planning to provide advices on DMPK, physicochemical profiles and safety pharmacology thanks to Takeda's experience and expertise in drug discovery and development. MMV is leading the project, in close partnership with Takeda, providing drug discovery and malaria biology expertise as well as strategic input to the project. MMV has also the responsibility to connect the project team with partners from the MMV network so that data on selected project compounds are available to aid decision making. Prof. Vicky Avery (Griffith University) and Prof. Susan Charman (Center for Drug Candidate Optimisation, Monash University) are MMV partners belonging to the project team with the respective responsibilities to deliver in vitro blood stage parasitology data and in vitro/ in vivo DMPK data on compounds selected by the team.
Others (including references if necessary)
1. World Health Organization (WHO). WORLD MALARIA REPORT 2015. (2015). DOI:ISBN 978 92 4 156515 8
2. Wells, T. N. C., Huijsduijnen, R. H. Van, Voorhis, W. C. Van, van Huijsduijnen, R. H. & Van Voorhis, W. C. Malaria medicines : a glass half full ? Nat. Rev. Drug Discov. 14, 424–442 (2016).
3. Meister, S. et al. Imaging of Plasmodium liver stages to drive next-generation antimalarial drug discovery. Science 334, 1372–7 (2011).
4. Duffy, S. & Avery, V. M. Development and optimization of a novel 384-well anti-malarial imaging assay validated for high-throughput screening. Am. J. Trop. Med. Hyg. 86, 84–92 (2012).
5. Lucantoni, L. & Avery, V. Whole-cell in vitro screening for gametocytocidal compounds. Future Med. Chem. 4, 2337–2360 (2012).
6. Wassermann, A. M. et al. Dark chemical matter as a promising starting point for drug lead discovery. Nat. Chem. Biol. (2015). doi:10.1038/nchembio.1936
7. Burrows, J. N., Duparc, S., Gutteridge, W. E., van Huijsduijnen, R. H., Kaszubska, W., Macintyre, F., Mazzuri, S., Möhrle, J. J. & Wells, T. N. C. New developments in anti-malarial target candidate amd product profiles. Malar. J. 16:26 (2017). DOI: 10.1186/s12936-016-1675-x
8. Katsuno, K. et al. Hit and lead criteria in drug discovery for infectious diseases of the developing world. Nat. Rev. Drug Discov. 14, 751–8 (2015).