Abstract
In the interest of identification of new kinase-targeting chemotypes for target and pathway analysis and drug discovery in Trypanosomal brucei, a high-throughput screen of 42,444 focused inhibitors from the GlaxoSmithKline screening collection was performed against parasite cell cultures and counter-screened against human hepatocarcinoma (HepG2) cells. In this way, we have identified 797 sub-micromolar inhibitors of T. brucei growth that are at least 100-fold selective over HepG2 cells. Importantly, 242 of these hit compounds acted rapidly in inhibiting cellular growth, 137 showed rapid cidality. A variety of in silico and in vitro physicochemical and drug metabolism properties were assessed, and human kinase selectivity data were obtained, and, based on these data, we prioritized three compounds for pharmacokinetic assessment and demonstrated parasitological cure of a murine bloodstream infection of T. brucei rhodesiense with one of these compounds (NEU-1053). This work represents a successful implementation of a unique industrial-academic collaboration model aimed at identification of high quality inhibitors that will provide the parasitology community with chemical matter that can be utilized to develop kinase-targeting tool compounds. Furthermore these results are expected to provide rich starting points for discovery of kinase-targeting tool compounds for T. brucei, and new HAT therapeutics discovery programs.
Highlights
Human African trypanosomiasis (HAT) is a parasitic infection that affects 10,000 patients annually [1]
Trypanosoma brucei, the parasite that causes sleeping sickness, is sensitive to a class of compounds called kinase inhibitors, and our project was aimed at identifying kinase-targeting compounds that rapidly and irreversibly inhibit parasite growth
This was accomplished by high-throughput screening of over 42,000 compounds, which resulted in identification of 797 potent inhibitors of parasite growth that are non-toxic to human cells
Summary
Human African trypanosomiasis (HAT) is a parasitic infection that affects 10,000 patients annually [1]. In response to repeated calls for new drugs from the World Health Organization and clear guidelines for new drug specifications for HAT[6], drug discovery efforts have increased worldwide for this otherwise neglected disease. The OpenLab Foundation was established in 2010 as a means to provide financial support to drug discovery efforts performed at GlaxoSmithKline (GSK) in collaboration with investigators outside the company who have identified new approaches to fighting tuberculosis[7], and tropical diseases such as HAT, malaria[8,9], Chagas disease, and leishmaniasis. In recent years large sets of screening data for compounds tested against the pathogens causing these diseases have emerged from this unique combination of industrial, philanthropic, and nonindustrial collaborators[7,8]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
