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.

Final Report

1. Project objective:

The project aimed to deliver a compound which met MMV’s Early Lead criteria and had potential for further elaboration into a preclinical candidate for treatment (TCP-1). Efforts were particularly focused on optimization of a screening hit with a benzimidazole core, which was compelling due to the series’ rapid rate of parasite killing (~Cq) and lack of discernible cross resistance with lab or filed strains.

2. Project design:

The project was designed around the hit molecule MMV1579683 having a benzimidazole core and a pendant basic group. Compound exploration led to two promising sub-series – monobasic and dibasic compounds -- each containing their own subset of compounds (amides, benzyl amines, and pyridyl-based targets).  The initial benzimidazole core was shown to be preferred over other heterocycles. The compounds that displayed good potency, and physicochemical and ADME properties were chosen for in vivo studies with the goal of obtaining a single-dose orally bioavailable drug. The best compound from in vivo studies was then subjected to an efficacy study.  

3. Results, lessons learned:

The original lead monobasic compound was found to have moderate potency (100 nM range) and CaCo-2 permeability with low clearance. This compound also displayed a similar mechanism of action compared to chloroquine, which was maintained in subsequent compounds. To achieve ideal potency (＜10 nM), the compounds required two basic nitrogen atoms (dibasic series). These compounds consistently displayed better potency than their monobasic counterparts and were found to be active against other strains of malaria. Despite poor permeability in the Caco-2 assay, several dibasic compounds were found to have good oral bioavailability (33-80%). The Caco-2 assay proved to be an unreliable method for predicting oral absorption for the series, likely to due to low compound recovery. The compounds showed very low metabolic clearance and good plasma half-life. While the dibasic amide series displayed the best overall profiles, their dibasic nature appeared to cause cytotoxicity in HepG2 cells, with both lead compounds displaying significant inhibition (HepG2 ＜10 uM). All of the compounds in the series also exhibited significant hERG inhibition (approx. 1 uM), which could not be mitigated by reducing the pKa of the basic centers, introducing polarity near the basic centers, or reducing overall lipophilicity. The productivity of the chemistry team was excellent over the course of the project and the team was able to thoroughly explore chemical diversity within the series. Representative examples of the series were tested throughout the program and shown to maintain the irresistible nature and mechanism of action similar to chloroquine. Unfortunately, due to the concerns of being unable to mitigate the safety risks posed by hERG inhibition and cell cytotoxicity the team’s conclusion is that it would not be possible to deliver a preclinical candidate, and the recommendation is to no longer pursue the series.