Introduction and Background of the Project

Introduction

The project builds on the successful hit validation of a compound series identified from a high-throughput screen of the Daiichi Sankyo library. The frontrunner compound demonstrated potent antimalarial activity and a novel mechanism of action. The current proposal aims to advance this series through Hit-to-Lead development, addressing key challenges such as metabolic stability and confirming the compound’s potential for malaria treatment and chemoprevention.

Project objective

The primary objective is to develop a compound series that meets GHIT HTLP/MMV Early Lead criteria. This includes demonstrating in vivo proof-of-concept efficacy and optimizing compounds for potency, stability, and drug-like properties suitable for further development.

Project design

The project involves iterative cycles of compound design, synthesis, and testing. The design strategy focuses on improving metabolic stability, maintaining high potency, and optimizing physicochemical properties. The team will explore scaffold modifications and structure-activity relationships (SAR) around key molecular positions to enhance drug-like characteristics while preserving efficacy.

How can your partnership (project) address global health challenges?

Malaria remains a major global health threat, with over 597,000 deaths in 2023, predominantly affecting children under five and pregnant women in sub-Saharan Africa. The emergence of resistance to frontline therapies such as artemisinin-based combination treatments (ACTs) underscores the urgent need for new drugs with novel mechanisms of action. The antimalarial target related to this project is a unique and essential protein in the parasite’s lifecycle, offering promise for both treatment and chemoprevention. By developing compounds with multi-stage activity, the project contributes to the global eradication agenda and aligns with MMV and WHO’s strategy for malaria control and elimination.

What sort of innovation are you bringing in your project?

This project capitalizes on the identification of a novel chemotype linked to a new mechanism of action. It leverages advanced medicinal chemistry and computational modeling to optimize the chemical series. The project also integrates predictive modelling tools and generative design platforms to streamline compound optimization.

Role and Responsibility of Each Partner

• Medicines for Malaria Venture (MMV): Designated development partner responsible for project leadership, timeline and budget adherence, GHIT reporting, and subcontracting key activities to an appropriate CRO (for chemistry synthesis, parasitology, cytotoxicity, and DMPK assays) and other MMV Network Partners (to support additional assays and safety profiling).

• Daiichi Sankyo: Providing in-kind support in compound design and SAR analysis.

Others (including references if necessary)

The project was supported by previous GHIT funding (S2020-113 and S2024-111) and aligns with MMV’s strategic goals.

Key references include:

“Global technical strategy for malaria 2016-2030, 2021 update”, WHO 2021