Introduction and Background of the Project

Introduction

In the fight against TB the number of drugs available is quite limited and many of them are 40 to 50 years old.  They need to be administered to the patients for at least 6 months in the best case and much longer in the case of drug-resistant TB.  New drugs are needed to shorten the treatment duration and to combat drug-resistant strains.  In order to identify prototypes of potential new TB drugs (hits) Takeda Pharmaceutical Company (Takeda) and TB Alliance jointly carried out screening campaigns.  We ultimately identified two series of compounds, one from phenotypic screening a large number of compounds with Takeda library for their ability to kill Mycobacterium tuberculosis (Mtb, the pathogen causing TB), and another from mechanism-based screening for their ability to inhibit a particular enzyme in Mtb from Takeda internal portfolio.  In this Hit-to-Lead project we intend to improve their potency and properties to make them suitable for treatment.

Project objective

The objectives of this project are to improve the potency of the hits to kill Mtb but at the same time to make them safe to be used in humans.  We also want to prove that the eventual drugs derived from these prototypes can be dosed orally and in reasonable doses to be widely accepted among TB patients worldwide.

Project design

To achieve these objectives, we will synthesize several dozens of analogues in each series to evaluate them in the assays related to the objectives above.  We will test selected analogues in mice to evaluate their activity in animal models.  The design, synthesis, and testing are an iterative process until we identify a compound best satisfying the objectives above.

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

More than 1.5 million people die from TB every year worldwide, and in order to decrease the suffering and the economic loss due to TB, we need novel drugs with increased efficacy, safety, and affordability.  Furthermore, to combat the emerging drug resistant strains we need drug with a new mechanism of action so that there is no preexisting resistance.  The two series in this project appear to have new mechanisms of action.

What sort of innovation are you bringing in your project?

In the series of the hits based on their ability to kill Mtb we are bringing in a new chemical series potentially possessing a novel mechanism to kill the pathogen.  We will determine the mechanism of killing Mtb and this knowledge can be used to search for additional chemical series having the same target but of different chemical structures.  In the series of the hits based on their ability to inhibit a specific enzyme in Mtb, this is the first attempt to find drugs inhibiting this specific enzyme in Mtb.  The structure of this enzyme in various bacteria are known and this information will enable us to utilize structure-based computational approaches in designing new analogues.

Role and Responsibility of Each Partner

The Takeda scientists will design new analogues to synthesize and apply their expertise in drug research and development to successfully navigate many stages of drug development.  The TB Alliance scientists will utilize their network of academic investigators and contract research organizations to synthesize and evaluate the analogues.  The design of the new analogues and their testing will be done in full consultation between the Takeda and TB Alliance groups.