Introduction and Background of the Project

Introduction

P. falciparum dihydroorotate dehydrogenase (DHODH) enzyme is a clinically validated target for the treatment of malaria. We have identified a novel azetidine chemical series that inhibits P. falciparum and P. vivax DHODH with high selectivity against the human ortholog. The series demonstrated activity against diverse clinical isolates of P. vivax and showed robust in vivo efficacy in P. berghei liver- and blood-stage models and in P. falciparum blood-stage models. The series has a good solubility, in vitro hepatocyte stability, and in vitro toxicity profile. The planned activities in this proposal will support the preclinical development of the azetidine series for the prophylactic and treatment purposes of malaria. 

Project objective

The objective of this proposal is to deliver a potent, safe and efficacious small molecule Plasmodium DHODH inhibitor as a clinical candidates which will fulfill Medicines for Malaria Venture’s (MMV) criteria for a prophylactic and/or treatment                                                                

Project design

The development strategies incorporate steps to optimize the potency, pharmacokinetic properties, in vivo efficacy and safety profile of our novel azetidine series to yield a clinical candidate that meets target product profiles defined by MMV.  Our proposed plan includes 1) Completion of structure-guided lead optimization of the azetidine scaffold to identify late lead(s), 2) Optimization of synthetic route and perform Chemistry, Manufacturing and Control (CMC) studies for the late lead(s) to produce Active Pharmaceutical Ingredient (API) to support nonclinical toxicology studies and 3) pharmacokinetic profiling and exploratory in vivo nonclinical toxicology studies of the late lead(s) to identify clinical candidate for Investigational New Drug (IND)-enabling GLP studies.

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

In order to decrease the morbidity and mortality associated with malaria, new chemotherapeutics that can target drug-resistant parasites are urgently needed. We anticipate that a candidate resulting from this pre-clinical development program will eventually be progressed to the clinic and, when co-administered with appropriate partner therapeutics (to reduce the likelihood of resistance emergence), will assist in the eradication of malaria malaria.

What sort of innovation are you bringing in your project?

P. falciparum DHODH enzyme is a clinically validated new target for the treatment of malaria. Our novel azetidine chemical series inhibits P. falciparum and P. vivax DHODH with high selectivity against the human ortholog. The series demonstrated activity against diverse clinical isolates of P. vivax and showed robust in vivo efficacy in P. berghei liver- and blood-stage models and in P. falciparum blood-stage models. We anticipate that a candidate resulting from this pre-clinical development program will fulfill Medicines for Malaria Venture’s (MMV) criteria for prophylactic and/or therapeutic and eventually be progressed to the clinic to assist in the eradication of malaria.

Role and Responsibility of Each Partner

Broad Institute is the designated development partner for the project. Project members from the Broad, Eisai and MMV will collaborate closely in order to execute the project plan while taking advantage of each organization’s strengths and expertise. Broad Institute will be responsible for directing the lead optimization campaign and medicinal chemistry efforts to identify the candidate with improved selectivity and safety profile. In addition, Broad will contribute to the identification of an optimized API synthetic process and monitoring scale-up API for preclinical studies. Eisai will be responsible for pharmacokinetics and all safety studies needed for candidate selection. Eisai will also contribute in the optimization of the API synthetic process, scale-up API for preclinical studies, salt selection and preliminary formulation studies. MMV will support the in vitro/ in vivo testing activities, life-cycle profiling, biochemical and X-ray co-crystal efforts, human dose prediction and play an advisory role.

Others (including references if necessary)

Maetani, M.; Kato, N.; Jabor, V. A.; Calil, F. A.; Nonato, M. C.; Scherer, C. A.; Schreiber, S. L. Discovery of antimalarial azetidine-2-carbonitriles that inhibit P. falciparum dihydroorotate dehydrogenase ACS Med. Chem. Lett. 2017, 8, 438-442.