- RFP Year2018
- Awarded Amount$1,922,475
- Development StageLead Optimization
- Collaboration PartnersMitsubishi Tanabe Pharma, Medicines for Malaria Venture (MMV)
- Past Project
Introduction and Background of the Project
Screening of an (approximately) 50,000 member library of unique compounds from the Mitsubishi Tanabe Pharma Corporation (MTPC) library identified several antimalarial hits from diverse series of molecules. Development of structure-activity relationships (SAR) for three series of focus (Series 1, 2 and 3) in a "Hit-to-Lead" project revealed that Series 1 was the most attractive series for further optimization, as the series is fast-killing, exhibits high antimalarial potency across the lifecycle (Target Candidate Profiles (TCP1,4 and 5) potential), has good physicochemical and pharmacokinetic properties and shows efficacy in the mouse model of malaria. Three of these Lead Compounds have formally met the MMV Early Lead criteria and will form the basis of this Lead Optimzation project.
The primary objective of the project will be to identify 1-3 late leads within 18 months, as defined by MMV’s progression criteria, and further profile them in the final 6 months to select a preclinical candidate capable of progression to first-in-human clinical trials. As an additional objective, the project will endeavor to confirm the proposed mode of action. By doing so, the project will be able to assess the likelihood that these compounds will have the ability to safely treat malaria in areas where resistance to existing drugs is emerging.
The project will be conducted as a multi-disciplinary drug discovery effort, utilizing the diverse skills and expereinces of medicinal chemists, molecular modelers, parasitologists, pharmacokineticists and toxicologists. Starting with the identified Early Lead Molecules, systematic modification of these drug candidates will be undertaken to further improve the pharmacological, selectivity, physicochemical, pharmacokinetic and toxicological properties based on state-of-the-art capabilities at MMV, MTPC and our partners. As the putative target of these molecules is an enzyme that is essential to the growth of the malaria parasite, and structural information is available from analogous bacterial proteins, a structure-based drug design (SBDD) approach will be applied. This will provide the opportunity to more rapidly focus on compounds with a higher likelihood of achieving the project objectives.
How can your partnership (project) address global health challenges?
Each year, the parasite Plasmodium falciparum causes more than 200 million cases of malaria, and over 400,000 deaths, mostly in children under 5 and pregnant women. Because current antimalarial control is highly dependent on artemisinin combination therapies (ACTs), it is extremely concerning that decreased parasite sensitivity has emerged to all currently used ACTs, leading to significant failure rates in parts of South East Asia where partner drug resistance is evident. If resistance becomes widespread in Africa (where most deaths occur), a major health crisis is feared. In response to this impending crisis and with the eventual aim of eradicating the disease, MMV seeks to discover, develop and deliver new drugs with novel modes of action which overcome all known resistance associated with existing therapeutics. Development of compounds which can block transmission and be used in chemo-protection/prevention, in addition to acute treatment, are especially valuable to drive the eradication agenda. The strength of this proposal lies in the parasitological profile of the series and its favourable drug-like properties, knowledge of the target which helps evaluate risk (including safety) and the proven track record of the scientific team, which should enable rapid development of this series to deliver a new preclinical candidate.
What sort of innovation are you bringing in your project?
In addition to the novelty of the lead series being pursued, the team will be using modern drug discovery approaches including structure-based drug design and protein crystallography to more rapidly identify a preclinical candidate from this project. This multidisciplinary approach has been successfully applied to projects within the MMV portofolio and promises to capitalize on the unique skills and experiences of scientists in both organizations.
Role and Responsibility of Each Partner
Both the MTPC and MMV teams will be fully integrated into the design, synthesis and evaluation of new compounds to achieve the project objectives. While the day-to-day laboratory work will be conducted at contract research organizations and academic partners, the overall scientific leadership will be jointly held by representatiaves of both organizations.
Others (including references if necessary)
- World Health Organization (WHO). WORLD MALARIA REPORT 2015. (2015). doi:ISBN 978 92 4 156515 8
- 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).
- Meister, S. et al. Imaging of Plasmodium liver stages to drive next-generation antimalarial drug discovery. Science 334, 1372–7 (2011).
- 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).
- Lucantoni, L. & Avery, V. Whole-cell in vitro screening for gametocytocidal compounds. Future Med. Chem. 4, 2337–2360 (2012).
- 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
- Burrows, J. N., van Huijsduijnen, R. H., Möhrle, J. J., Oeuvray, C. & Wells, T. N. C. Designing the next generation of medicines for malaria control and eradication. Malar. J. 12, 187 (2013).
- 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).