Principal Investigator (PI)
NEU/CSIC
The Foundation is providing £99,100 in support.
NA
Expertise in drug discovery (included ADMET expertise) with the aim of accelerating the discovery of a pre-candidate for HAT
Performance of in vitro ADME experiments (solubility, permeability, microsomal stability, plasma protein binding, MDCK-MDR1, CYP inhibition; up to 3-5 compounds/mo)
Mouse PK experiments at GSK, with plasma drug levels (up to 10 per year).
Safety profiling (EXP) – up to 4 compounds/year
GSK is assembling a “HAT-box” with 192 compounds with submicromolar activity against Tbb and selectivity over human cells coming from the HTS campaign of the GSK collection. These compounds could be used also as starting points if needed.
From December, 2011 - March, 2013 a TCOLF-funded collaboration between GSK-Tes Cantos, Northeastern University (NEU), and CSIC was undertaken in order to assess a kinase targeted library for anti-T. brucei activity. Following the screening of ~42k compounds, the project team identified 797 potent (pIC50>6), selective (>100x over HepG2 cells) inhibitors of T. brucei growth in vitro. These compounds were characterized in terms of their rate of killing, reversibility (cidality), and for their computed properties (including prediction of CNS penetration). These culminated in mouse PK studies, and efficacy was demonstrated for one HTS hit (SB-443342), which effected cure of a bloodstream infection following an IP dosing regimen at 10 mg/kg. (PLOS-NTDs, 2014 e3253). On the strength of these data, the NEU and CSIC investigators have secured five years of funding from the US NIH ($2.5 million award total costs) to translate these hit compounds into advanced lead compounds that show potent and non-toxic efficacy in mice with CNS T. brucei infections following oral dosing. The main objective of the Open Lab is to assess the likelihood of these leads to be Candidates, with that aim and given the difficulties associated with accessing some of the required drug discovery expertise and capacity in an academic environment and the unique value offered through the Open Lab program, we now request periodic support for the ADME, PK, and toxicity studies needed in order to advance this project towards the delivery of a clinical candidate against sleeping sickness