Introduction and Background of the Project

Shionogi, Japan Anti-tuberculosis Association (JATA), and Global Alliance for TB Drug Development (GATB) have had a collaborative relationship in the screening program of anti-TB compounds supported by the GHIT Fund. We have successfully identified 3 series of hit compounds through our screening program that started with approximately 40,000 compounds of a low molecular weight compound library owned by Shionogi. The representative novel hits exhibit sufficient anti-TB activities under both of aerobic and anaerobic conditions with less cytotoxicity, showing efficient killing of non-replicating persister population of Mycobacterium tuberculosis. Furthermore, the hit compounds show equally potent activity against multi-drug resistant (MDR) and extensively-drug resistant (XDR) strains tested.
The objective of this program is to discover novel chemical lead series having 1) activity against drug-sensitive TB strains; 2) activities against MDR- and XDR-TB; and 3) the potential for shortening the duration of chemotherapy. After generating profiles of those hit series by generating the structure activity relationships (SAR) information and collecting the pharmacophore data and determining the Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) profiles, we expect to pick one or two series to focus the identification of a lead compound on.

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

According to the resent WHO’s global TB report, an estimated 9.0 million people developed TB and 1.5 million died from the disease in 2013 (including 360,000 deaths from HIV-positive people). One of the most serious public health problems in the world currently is MDR-TB because of the lack of effective anti-MDR-TB drugs. The WHO estimated that about 480,000 people developed MDR-TB globally in 2013. The proportion of XDR-TB is now estimated to comprise 9.0% of MDR-TB patients and the poor MDR-TB treatment outcomes (48% success rate) are major concern. Also, there are further complications for patients who are co-infected with HIV because of the drug-drug interactions between commonly used antiretrovirals and first-line anti-TB drugs. The disease disproportionately impacts people in their most productive years is the major factor inhibiting economic and social growth of the developing countries. In fact, TB is the number one killer of people living with HIV, accounting for 1 in 4 deaths.
What is needed to improve patient compliance is particularly difficult given the long treatment period (typically 6 months for drug-sensitive TB and more than 18 months for drug-resistant TB).
It is expected that the novel lead compounds identified from this program of improving hit series have potential impact with the following needs to control the global TB program: (1) by providing a new TB drug with a novel mechanism of action to combat the rising drug resistance problem; (2) by shortening the treatment duration; (3) by improving patient compliance; (4) by providing additional choices for new drug combination regimens for MDR- and XDR-TB, TB/HIV, and Latent TB cases; (5) by reducing overall medical expenditures (especially in high burden developing countries).

What sort of innovation are you bringing in your project?

We have successfully identified hit compounds having novel structures and showing efficient killing of M. tuberculosis under anaerobic condition, which mean the lead compounds developed from these hits would have the potencies to overcome problems of drug resistance such as MDR- and XDR-TB and long duration for TB cure. Additionally, among the promising hit compounds, while not in the antibacterial class, were already under assessment in Shionogi’s internal programs, which means there is already in-depth knowledge of their chemistry and ADMET.

Others (including references if necessary)

WHO Global Tuberculosis Report 2014 (accessed 09 Apr 2015), http://www.who.int/tb/publications/global_report/en/index.html

Final Report

1. Project objective

Shionogi, Japan Anti-tuberculosis Association, and Global Alliance for TB Drug Development have had a collaborative relationship in the screening program of anti-TB compounds supported by the GHIT Fund. We have successfully identified 3 series of hit compounds. The objective of this program was to discover novel chemical lead series having 1) activity against drug-sensitive TB strains; 2) activities against MDR- and XDR-TB; and 3) the potential for shortening the duration of chemotherapy.

2. Project design

In this Hit-to-Lead project, we plan to generate profiles of those hit series by generating the SAR information, collecting the pharmacophore data and determining the ADMET profiles. And then, we expect to pick one or two series to prioritize and progress to the in vivo safety and efficacy study in a mouse acute infection model. After the profiling and subsequent SAR of the prioritized series to grasp their issues, we will identify at least one lead which meets the GHIT Fund’s Lead criteria at the end of the research period.

3. Results, lessons learned

SAR information of the three hit series was confirmed in the first half year of this project. One series, especially, which was in Shionogi’s non-antibacterial drug discovery program appeared to have highly potent anti-TB activities. This series exhibited excellent in vitro anti-TB activity with a sufficient selectivity as shown by the spread between the activity and cytotoxicity. Also, they showed acceptable in vitro ADMET profiles and good pharmacokinetic potentials in rodents. During the second half year of this project, we focused on this series as a lead candidate series to improve the profiles and to identify their ADMET profiles. In this regard, we expected to rapidly progress this project by utilizing our existing knowledge of the series with respect to the ADMET profiles. We have achieved a substantial increase in in vitro potency and a preliminary evaluation of its safety. Furthermore, the compounds showed potent activity in a mouse acute Mtb infection model and met the GHIT Fund’s Lead criteria. After synthesis of additional analogues, we successfully improved the solubility while maintaining good potency against TB, and we have found some compounds with improved CYP inhibitory profiles, which may be related to the reduced lipophilicity.

However, this series was discontinued because of the reproducibility problem of its in vitro activity despite our efforts to investigate the cause and to find substitutive assay conditions. We plan to investigate a farther development of remaining our hit series as another project from now on.