The scientist: Dr. Abraham Lopez will focus his research on the optimization of several hits coming from intracellular high-throughput screening (HTS) against Mtb-infected macrophages. Abraham is a Postdoctoral Researcher with significant previous experience in drug discovery, working under the supervision of Prof. Av-Gay. He is an organic/medicinal chemist by training, and his primary objective in this project will be the delivery of new compounds with good activity in macrophages, acceptable ADME and safety profiles, and with a potential indication of in vivo efficacy for further progression to a lead optimization stage.
The sponsor: University of British Columbia
Foundation funding: The Foundation is providing £135,680 in support.
GSK’s contribution: GSK will contribute its extensive biological and medicinal chemistry experience in whole cell programs for TB (ChemMedChem 2013,8, 313; PlosOne, PLoS One 2013, 8(4), e60933) and will provide access to the existing tools for the drug discovery process.
Project Description: The phenotypic approach for the discovery of new anti-TB drugs relies on the screening of compound libraries against Mtb in in-vitro artificial growth conditions. However, those conditions do not resemble the physiological environment in human macrophages, which is one of the hallmarks of Mtb pathogenesis.
The group of Prof. Av-Gay has recently carried out a TCOLF-funded HTS against Mtb-infected human macrophages. This activity led to promising identified hits, showing inhibition of bacteria growth at low micromolar concentrations with a remarkable 2 orders of magnitude increase in intra-macrophage activity compared to the in-vitro whole cell assay.
The initial stage of this program will involve early stage in-vitro TB biology and ADMET profiling of selected hits. Initial synthetic efforts will focus on a limited set of target compounds to define the minimum pharmacophore, identify issues and demonstrate the scope for a more extensive hit to lead (H2L) plan to address the issues. The H2L process typically requires a number of synthesis rounds (≈50 compounds). In order to enter lead optimization, the series should be significantly de-risked, demonstrated in-vivo efficacy and have a suitable probability of delivering an optimized lead compound. In addition to this work, a detailed study on the mechanism of action will be carried out in parallel, potentially leading to the discovery of a novel drug target for TB.