Introduction and Background of the Project

Introduction

Malaria, a mosquito-borne disease caused by Plasmodium parasites, still infects over 228 million people per year. There were an estimated 405,000 malaria deaths worldwide in 2018 (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 tools needed to meet the malaria eradication agenda (2).　The project team is now working on prolyl tRNA Synthetase (PRS) Inhibitors with the aim of identifying a potential new antimalarial drug. This PRS chemical series was directly repurposed from the Takeda Pharmaceutical Company Limited (Takeda) portfolio. At the beginning of the collaboration between Takeda and Medicines for Malaria Venture (MMV), screenings were performed at MMV testing centers in the USA (Prof. Elizabeth 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. Data gathered showed that the Takeda PRS chemical series has activity against both the asexual blood and liver stages of the Plasmodium lifecycle.

Project objective

The main objective of the project is to transform PRS Inhibitors into Lead series with proven in vivo efficacy in relevant animal disease models so as to identify at least one compound as an early lead molecule that meets the GHIT/MMV criteria for progression to Lead Optimization stage for prophylaxis.

Project design

This project will follow the current hit-to lead activity that will end in October 2020. In this new phase the project team will perform medicinal chemistry activity to optimise the PRS chemical series in terms of DMPK and physicochemical properties to meet GHIT/MMV early lead criteria. The most promising compounds will be evaluated in rodent PK experiments and in a relevant model of malaria to demonstrate in vivo efficacy/protection. 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. In the absence of a highly effective vaccine, new drugs are needed to protect patient populations in the context of the malaria eradication agenda endorsed by the Bill and Melinda Gates Foundation and the WHO. Unfortunately, the current pipeline lacks compounds that can be used as novel prophylactic agents. 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 collaborative project between Takeda, MMV and GHIT is focused on delivering compounds that meet TCP4 criteria (prophylaxis) through delivery of a chemoprotective agent capable of protecting vulnerable populations from reinfection.

What sort of innovation are you bringing in your project?

Although PRS is a clinically validated target, there are currently no antimalarial drugs acting through this mechanism of action (7). The PRS series benefits from dual asexual blood and liver stage activities and could fill strategic gaps in the MMV portfolio with respect to novel prophylactic agents. This chemical 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. Takeda's role is to lead this project and to make scientific inputs for the medicinal chemistry plans, the selection of analogues for further studies and the profiling of the hit chemical series in MMV testing centers. Takeda is also planning to provide advices on DMPK, physicochemical profiles and safety pharmacology based on Takeda's experience and expertise in drug discovery and development. MMV's role is to provide drug discovery and malaria biology expertise as well as strategic input to the project.

Others (including references if necessary)

(1) World Health Organization (WHO). WORLD MALARIA REPORT 2019. (2019). ISBN: 978-92-4-156572-1

(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) 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) Nyamai, D. W., Bishop, O. T. Identification of Selective Novel Hits against Plasmodium falciparum Prolyl tRNA Synthetase Active Site and a Predicted Allosteric Site Using In Silico Approaches Int. J. Mol. Sci. 21, 3803 (2020).

(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).

Final Report

1. Project objective

The main objective of the project was to transform PRS Inhibitors into Lead series with proven in vivo efficacy in relevant animal disease models so as to identify at least one compound as an early lead molecule that meets the GHIT/MMV criteria for progression to Lead Optimization stage for chemoprevention.

2. Project design

This project followed previous hit-to lead activity in H2018-101 that ended in Sep 2020. In the phase of H2020-101, project team performed medicinal chemistry activity to brush up PRS chemical series in terms of drug like properties to meet GHIT/MMV early lead criteria. The most promising compounds were evaluated in rodents PK experiments and in the disease model of human malaria to demonstrate in vivo efficacy. The goal was to select a couple of lead molecules which would be the basis of a new proposal to GHIT for a Lead Optimization program.

3. Results, lessons learned

In the phase of H2020-101, the project team had focused on structural optimization of advanced chemical series identified in H2018-101, with the goal of continuing to discover candidate molecules that meet the early lead criteria set by GHIT and MMV. Since MMV1796177 identified in the previous phase (H2018-101) was a highly safe compound that did not inhibit human Prolyl-tRNA synthetase but showed inhibitory activity against Plasmodium prolyl-tRNA synthetase, the project team had focused on optimizing the balance of physicochemical properties, metabolic stability, cytotoxicity, and pharmacokinetic ADMET properties while maintaining the PRS selectivity profile of MMV1796177.

MMV1902882 was identified during the optimization process in H2020-101 and was found to inhibit more potently the growth of malaria parasites than MMV1796177 at the blood stage in the life cycle of malaria parasites (3D/ IC50 70 nM) with an acceptable PK profile in mouse at this early stage (oral bioavailability 22%, MRT p.o. 2.9 h) Therefore, an in vivo experiment with 6-day treatment of oral administration (100 mg/kg, qd) was conducted using a human malaria infection model mouse, and then we confirmed that significant antimalarial activity was observed compared to the experimental control group.

Overall, MMV1902882 met the early lead criteria set by GHIT and MMV and appear suitable for further structural optimization. The project team submitted a GHIT PDP application in July 2022 with the goal to start lead optimization in April 2023.