Development of Phenotypic Screening Hits against Mycobacterium tuberculosis
  • Awarded Year
    2015
  • Awarded Amount
    $792,165
  • Disease
    Tuberculosis
  • Intervention
    Drug
  • Development Stage
    Lead Identification
  • Collaboration Partners
    Takeda Pharmaceutical Company Limited, The Global Alliance for TB Drug Development

Introduction and Background of the Project

Tuberculosis has caused untold number of human deaths throughout history and continues to plague the world today, disproportionally affecting the poor. According to the WHO, in 2014 there were an estimated 9.5 million new cases of TB and 1.5 million deaths. In spite of the enormous human toll current treatment is long and complex, and resistant forms of the disease have developed for which there is no effective cure. The pathogen, Mycobacterium tuberculosis (M tb), is so well-adapted to infecting humans that modern science is just beginning to catch up with the disease. Today's TB treatments are complicated to administer, long, and can be toxic. Treatment for drug-resistant TB can take up to two years, and is so difficult, expensive, and noxious that many patients are unable to access treatment. Treating MDR-TB can literally be thousands of times as expensive as that of regular treatment in some regions — posing a significant challenge to governments, health systems, and other payers. Of those who do, almost half will die. The joint TB Alliance-Takeda research program sets out to identify candidate compounds from Takeda's proprietary compound libraries that will kill M tb with new mechanisms of action. Novel drugs, and regimens of multiple novel agents that can shorten treatment and be used in combination with antiretroviral drugs are desperately neeeded to improve the treatment landscape for those suffering from TB.

 

The objectives of the proposed collaboration between TB Alliance and Takeda, the largest Japanese pharmaceutical companyliance will coordinate all the activities nare to expand the chemistry work on hit series identified by screening a library of 20,000 of Takeda’s proprietary compounds. We will make sure they have a new mechanism of action so that they can be expected to work against resistant Mtb and to contribute in treatment shortening.  This includes design and synthesis of the analogues of the hit series and testing the analogues for their activity against Mycobacterium tuberculosis (Mtb).  The analogues will be further manipulated to have a reasonable metabolic profile so that we can demonstrate their activity in mice which will set the stage for the next phase of drug discovery called lead optimization. 

 

The project will begin synthesizing new analogues based on the hits discovered in the screening Takeda's proprietary compounds.  Using the know-how accumulated in Takeda new analogues will be designed to improve their activity and safety.  The designed compounds will be synthesized by working with a CRO in China and tested against Mtb in the University of Illinois. From the data generated new analogues will be designed and prepared.  Through this iterative process the potency and safety of the analogues will improved so that we can test their activity in vivo.  The compounds' mechanism of action will be examine to show they have new mechanisms of action to ensure they will be useful against resistant Mtb. 

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

By targeting compounds with novel mechanisms of action we can contribute toward obtaining new drugs against TB.  It will help combating the drug resistant forms of this disease and to shoten the treatment duration so that more patients will comply and be cured.  

What sort of innovation are you bringing in your project?

Takeda has worked on these series of compounds for other therapeutic areas and they have accumulated knowledge on them which can now be applied to designing new TB drugs.  TB Alliance has an extensive network of TB drug researchers and it can mobilize them in testing new analogues using the latest technology for their mechanism of action and efficacy in vitro and in vivo.

Role and Responsibility of Each Partner

Takeda scientists will contribute their know how in drug discovery toward developing these compounds and TB Alliance will coordinate all the activities necessary for developing these hits including their synthesis, testing against Mtb, and their preliminary drug metabolism and toxicology profiles, and demonstrating their activity in mice.