Introduction and Background of the Project

Introduction

Tuberculosis (TB) is the leading cause of death from infectious disease worldwide. The Broad Institute has identified a novel azetidine compound series that inhibits the growth of M. tuberculosis (Mtb) by phenotypic whole-cell screening of the Broad Institute’s Diversity Oriented Synthesis (DOS) library compound collection against log-phase Mtb. The compound series inhibits the growth of Mtb by allosterically inhibiting Mtb tryptophan synthase. Mtb tryptophan synthase is an essential metabolic enzyme required for Mtb survival but absent in humans. The compound series demonstrate activity against non-replicating Mtb and a panel of geographically diverse clinical isolates of Mtb, including multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB). Profiling of analogs in the acute Mtb mouse model showed in vivo activity.    

Project objective

The objective of this proposal is to deliver a potent, safe and efficacious small-molecule allosteric inhibitor of Mtb tryptophan synthase with good physicochemical and pharmacokinetic properties suitable for pre-clinical development for the treatment of tuberculosis.  

Project design

Our project design is to optimize the potency, pharmacokinetic properties, in vivo efficacy and safety profile of our novel azetidine series to yield a late lead candidate that meets target product profiles for pre-clinical development defined by TB Alliance for the treatment of tuberculosis. Our Objectives include 1) to design and synthesize new analogs with improved in vivo efficacy in a TB mouse model and establish PK/PD relationship; 2) to determine in vivo efficacy in chronic and C3HeB/FeJ TB models with compounds having improved MIC and efficacy in acute model; and 3) to assess in vitro and in vivo safety liabilities to select short-list compounds.    

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

The bacteria Mycobacterium tuberculosis (Mtb) is responsible for the airborne disease Tuberculosis (TB) which is the leading cause of death from infectious disease worldwide surpassing HIV. HIV/AIDS patient populations are disproportionately more vulnerable to suffer from TB due to compromised immune systems. The standard of care consists of long-term treatment (6-9 months) of a multi-drug regimen leading to poor patient compliance. Multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) require even longer therapeutic intervention (2 years). We believe that development of a novel mechanism-of-action allosteric inhibitor of Mtb tryptophan synthase based on our azetidine series will provide a significant advantage to overcome the global rise of resistance against current prescribed standard of care drugs and will shorten the treatment time of TB when co-administered with appropriate partner therapeutics. 

What sort of innovation are you bringing in your project?

The therapeutic intervention for multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) consists of long-term treatment (2-years or more) leading to poor patient compliance and mortality. Additionally, M. tuberculosis (Mtb) in human host often adopts to a non-replicating dormant stage which exhibits tolerance to standard antibiotic therapy. One of the most effective ways to treat drug-resistant TB with shorter treatment duration time is to develop new drugs with novel mechanisms of action demonstrating activity against non-replicating Mtb. Our azetidine series works through a novel mechanism of action and allosterically inhibits previously untargeted essential metabolic enzyme Mtb tryptophan synthase. As the target/pathway is absent in human, it’s an attractive target for therapeutic intervention.  Additionally, the series demonstrated activity against non-replicating Mtb and against geographically diverse clinical isolates of MDR and XDR-TB strains.    

Role and Responsibility of Each Partner

Broad Institute is the designated development partner for the project. Project members from the Broad Institute, Eisai, Colorado State University (CSU), University of Chicago and TB Alliance 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 preparing and directing the Lead Optimization plan to identify compounds with improved potency and pharmacokinetic profile.

Eisai will support the medicinal chemistry efforts, DMPK experimental work and safety studies.

CSU will be responsible for all in vitro MIC testing and in vivo efficacy studies.  

The University of Chicago will be responsible for X-ray crystallography efforts to guide the structure based lead optimization effort.

TB Alliance will advise and coordinate the overall project activities.

Additionally, we will have periodic teleconference with TB Drug Accelerator (TBDA) to share progress and discuss scientific directions.     

Others (including references if necessary)

Wellington, S.; Nag, P.P.; Michalska, K.; Johnston, S. E.; Jedrzejczak, R. P.; Kaushik, V. K.; Clatworthy, A. E.; Siddiqi, N.; McCarren, P.; Barjami, B.; Maltseva, N. I.; Fisher, S. L.; Joachimiak, A.; Schreiber, S. L.; Hung, D. T. Identification of a specific allosteric small-molecule inhibitor of Mycobacterium tuberculosis tryptophan synthase Nature Chemical Biology 2017, 13, 943-950.