Introduction and Background of the Project

Introduction

MMV1579683 is an ‘Irresistible’ Benzimidazole identified from a phenotypic screen of a Takeda compound library against P.falciparum blood stages.

Project objective

The objective will be to perform Hit-to-Lead studies to deliver a compound from this series which meets MMV’s Early Lead criteria (https://www.mmv.org/research-development/information-scientists) and which has the potential to enter lead optimization to ultimately deliver a preclinical candidate suitable for treatment of malaria (TCP-1) as a component of a drug combination.

Project design

• ・Establish structure activity relationships to demonstrate improved potency is possible (3D7 EC50 < 100nM), while maintaining a good selectivity window against human cell lines (HepG2 EC50 >10 uM) and good lead-like qualities for an oral agent: Mwt < 500 and good solubility and permeability.
• ・Profile in-vitro ADMET properties and identify potential liabilities e.g hERG inhibition, metabolism and CYP inhibition. Apply appropriate MedChem risk mitigation strategies as required.
• ・Conduct pharmacokinetic experiments on representative compounds to investigate IVIVC and provide support for a reasonable expectation of achieving robust oral bioavailability (demonstrate F > 50% in Rat) and long half-life in human (target for Rat t1/2 >8h).
• ・Conduct all necessary studies required to profile one or more frontrunners against the MMV Early Lead criteria, including oral efficacy in an in-vivo model of malaria.
• ・Establish a clear path for IP. 

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

The vision of the WHO and MMV is to reduce deaths from malaria and ultimately eliminate the disease. There is an urgent need to provide new affordable medicines that address the resistance which is emerging against current drugs that treat, or protect against, malaria. New drugs for treatment of malaria are aimed to be single dose combinations with improved dosing regimen and lower cost compared to the Standard of Care (i.e. Artemesin-Lumefantrin). There is now a robust global portfolio of clinical candidates which have the potential to deliver on this objective. However, there is always attrition which requires us to keep fueling the pipeline. To reduce the risks of resistance occurring we are now prioritizing ‘irresistible’ series in the discovery phase as we believe they will be good partners for existing and future candidates. Irresistible series are rarely identified and make up only a small portion of the MMV discovery portfolio (i.e. 6/29 series in the 2022 portfolio).

What sort of innovation are you bringing in your project?

The project brings forward an ‘irresistible’ series which has an attractive parasitological profile and drug-like properties in the context of a team which has a track-record of drug discovery that delivers preclinical candidates.

Role and Responsibility of Each Partner

Takeda discovery scientists will lead the Medchem design, manage compound synthesis and collection of ADMET data, help prepare H2L progress reports and lead decision-making via monthly meetings of the Joint Project Team. MMV will be responsible for the performance of the project, manage the project budget, providing financial reports according to GHIT reporting cycles. MMV will also provide strategic advice to ensure the project delivers on the objectives. MMV will also provide access to its extensive screening platform through its partner network.