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Awarded Amount$445,500DiseaseMalariaInterventionDrugDevelopment StageLead IdentificationCollaboration PartnersSumitomo Dainippon Pharma Co., Ltd. , Medicines for Malaria Venture (MMV)Past Project
Introduction and Background of the Project
Malaria is a mosquito-borne disease that infects more than 200 million people every year. In 2016, the disease caused an estimated 445,000 deaths worldwide. The vast majority of those who lost their lives were children under the age of 5 years (1). Novel classes of antimalarial medicines targeting different parasite stages are urgently needed to provide both effective alternatives to current therapies falling prey to resistance, and to provide pharmaceutical tools to meet the malaria eradication agenda (2).
This project originates from a GHIT-funded screening of a 28,810-compound library selected from Sumitomo’s library. The screening was performed at MMV testing centers in Australia (by Prof. Vicky Avery at Griffith Institute for Drug Discovery, Griffith University) and in USA (by Prof. Winzeler at the University of California, San Diego) against the blood-stage, (asexual (3) and sexual (4)) and the liver stage (5) of the malaria parasite. In parallel, the activity of the compounds was measured in cellular models of human toxicity. Several novel series were identified, and in 2017 further profiling as well as expansion of hit series was conducted to further understand their biological profile and structure activity. Pharmacokinetic and physicochemical measurements were also conducted. The project is now at the Hit-to-Lead phase with four series. All four series show good potency in whole cell blood-stage assays; in addition, two series show good activity in both liver-stage and gametocyte formation assays.
The objective of this project is to transform at least one series identified through the high-throughput screening, into a Lead series with in vivo activity in an animal disease model before April 2019. The series will need to meet GHIT/MMV criteria for progression to Lead Optimization stage. Further work will be performed during the Hit-to-Lead phase to understand the activity of the series in the parasite lifecycle and alignment to Target Candidate Profiles (TCP).
During the first phase of the project, work to improve specific properties of each series to meet Lead Optimization criteria will be performed. Examples of such properties are potency in biological models of malaria parasite, pharmacokinetic properties, especially metabolic stability and physicochemical properties, such as solubility. Also, work will be undertaken to try to identify the mechanism of action for the series. Finally, frontrunner compounds from the four series selected for Hit-to-Lead progression will be profiled in the pharmacological models of the parasite lifecycle to confirm their alignment to Target Candidate Profiles (TCPs) (6). The most promising compounds will be evaluated in rodent PK experiments and in the disease model of human malaria to demonstrate in vivo efficacy. The goal is to select several lead molecules that will form the basis of a new proposal to GHIT for a Lead Optimization program.
How can your partnership (project) address global health challenges?
Malaria remains a significant life-threating disease. The majority of the almost half million malaria-related deaths are of young children, mainly in African countries. The global community is jointly working towards a common goal, the eradication of malaria. In this fight new medicines are essential weapons. Significant improvements can still be made over the current gold standard, artemisinin combination therapies. For example, there is a need for combination medicines in single-dose regimens that are safer and more effective. In the context of malaria eradication, 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.
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 (6). This project 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) anti-relapse for patients infected with Plasmodium vivax and Plasmodium ovale
iii) transmission blocking by targeting the host gametocyte population and
preventing infection to the mosquito
iv) chemoprotection capable of protecting vulnerable populations from reinfection.
The profiles from pharmacological studies during hit evaluation indicate that series have the potential to meet one or several of these targets. Finally, the Hit-to-Lead phase aims to also develop compounds able to show a long-acting profile.
What sort of innovation are you bringing in your project?
All the compound series being explored have been prioritized based on novelty of the chemotype, life-cycle fingerprint (in particular, activity on gametocytes 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 (7) and offer differentiation compared to existing series in the MMV portfolio at the time of the LO proposal.
All series have novel drug-like chemotypes, different from current antimalarial drugs in use or compounds in the clinical pipeline. Their mode of action will also be studied in the Hit-to-Lead phase.
Role and Responsibility of Each Partner
The project team consists of drug discovery and medicinal chemistry experts from Sumitomo Dainippon Pharma and MMV as well as parasitology and DMPK specialists from within the MMV network. The role of project members from Sumitomo Dainippon Pharma, together with scientists from MMV, Griffith University and Monash University, is to provide scientific input into the medicinal chemistry plans, the selection of analogues for further studies and the profiling of the hit chemical series. MMV is leading the project, in close partnership with Sumitomo Dainippon Pharma, providing drug discovery and malaria expertise as well as strategic input to the project. MMV is also responsible for connecting the project team with partners from its network so that data on selected project compounds are available to aid decision making. MMV partners, Prof. Vicky Avery (Griffith University) and Prof. Susan Charman (Center for Drug Candidate Optimization, Monash University) are members of the project team, and are responsible for delivering in vitro blood stage parasitology data and in vitro / in vivo DMPK data, respectively, 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. 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).
4. Lucantoni, L. & Avery, V. Whole-cell in vitro screening for gametocytocidal compounds. Future Med. Chem. 4, 2337–2360 (2012).
5. Meister, S. et al. Imaging of Plasmodium liver stages to drive next-generation antimalarial drug discovery. Science 334, 1372–7 (2011).
6. 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
7. 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).
1. Project objective
The objective of this project was to transform at least one out of four series identified through high-throughput screening, into a Lead series with in vivo activity in an animal disease model before April 2019. The series should meet GHIT/MMV criteria for progression to Lead Optimization stage. During the Hit-to-Lead phase, work should be made to confirm and further understand the activity of series in the parasite lifecycle and their alignment to Target Candidate Profiles (TCPs).
2. Project design
Work to improve specific properties of each series to meet Lead Optimization criteria was performed. Examples of such properties are potency in biological models of malaria parasite and pharmacokinetic properties. Compounds from the two highest rated series was profiled in pharmacological models of the parasite lifecycle to confirm their alignment to TCPs. Promising compounds was evaluated in rodent PK experiments aiming to support planning for studies in a disease model of human malaria to demonstrate in vivo efficacy. Finaly, work was undertaken to identify the mechanism of action for two of the series.
3. Results, lessons learned
Focus in the project has been on the two top series, since biologic profiling indicated both series had potential as blood stage, liver stage and transmission blocking therapies. For series 1, objectives in Hit-to-Lead were to improve potency in asexual blood stage assays and to improve metabolic stability. The fine physical chemical properties of series should be retained. However, potency has not been improved in Hit-to-Lead and best compounds are still in range of the starting point. In general series have had issues with regard to either: efflux, metabolic stability or permeability, though there has been some progress regarding PK properties. Metabolites often show similar biological activity as parent, this has been explored in PK studies to study potential of the series as pro-drugs. Transmission blocking potential was confirmed in the SMFA model with excellent activity of the compound tested. Secondary pharmacology screening confirmed a very good selectivity profile. Searching for mode of resistance revealed that the series did show sensitivity to known resistance mechanisms.
A main objective in Hit-to-Lead for series 2 was to improve potency in asexual blood stage assays, while properties such as good solubility should be retained. However, potency has not been improved in Hit-to-Lead and best compounds are in range of the starting point. With regard to PK, the series had some important benefits over series 1. Good exposure in mice after oral dosing was obtained and the series was also much more amenable for synthesis. Transmission blocking potential was confirmed in the SMFA model. Secondary pharmacology screening showed significant cross over to other targets in the panel. Searching for mode of resistance on STPHs resistant strain models revealed no significant sensitivity to any of the strains.
One learning from this project has been to keep down numbers of series at the start. Series 3 and 4 was worked upon during the first six months of project. In retrospect, these series were a distraction. A second learning is to fully consider the burden of complex synthetic chemistry at the initiation; this led to long and few design cycles for one of the series.