Human African trypanosomiasis (HAT) is a neglected tropical disease caused by the protozoan parasite Trypanosoma brucei. Because drugs in use against HAT are toxic and require intravenous dosing, new ...drugs are needed. Initiating lead discovery campaigns by using chemical scaffolds from drugs approved for other indications can speed up drug discovery for neglected diseases. We demonstrated recently that the 4-anilinoquinazolines lapatinib (GW572016, 1) and canertinib (CI-1033) kill T. brucei with low micromolar EC50 values. We now report promising activity of analogues of 1, which provided an excellent starting point for optimization of the chemotype. Our compound optimization that has led to synthesis of several potent 4-anilinoquinazolines, including NEU617, 23a, a highly potent, orally bioavailable inhibitor of trypanosome replication. At the cellular level, 23a blocks duplication of the kinetoplast and arrests cytokinesis, making it a new chemical tool for studying regulation of the trypanosome cell cycle.
Human African trypanosomiasis (HAT) is a neglected tropical disease caused by the protozoan parasite Trypanosoma brucei . Because drugs in use against HAT are toxic and require intravenous dosing, ...new drugs are needed. Initiating lead discovery campaigns by using chemical scaffolds from drugs approved for other indications can speed up drug discovery for neglected diseases. We demonstrated recently that the 4-anilinoquinazolines lapatinib (GW572016, 1) and canertinib (CI-1033) kill T. brucei with low micromolar EC50 values. We now report promising activity of analogues of 1, which provided an excellent starting point for optimization of the chemotype. Our compound optimization that has led to synthesis of several potent 4-anilinoquinazolines, including NEU617, 23a, a highly potent, orally bioavailable inhibitor of trypanosome replication. At the cellular level, 23a blocks duplication of the kinetoplast and arrests cytokinesis, making it a new chemical tool for studying regulation of the trypanosome cell cycle.
Malaria is one of the most devastating infectious diseases causing 1-3 million fatalities a year. The majority of these cases occur amongst children in developing countries. Malarial strains in these ...areas are exhibiting increasing resistance to canonical treatments proving the importance of new drug targets for anti-malarials. Identification of new drug targets is dependent upon a better understanding of the molecular biology of the parasitic agent of malaria, Plasmodium. The regulation of Plasmodium's complex life cycle is still not well understood. Elucidation of signaling pathways involved in Plasmodium cell cycle regulation will provide insights into how the parasite thrives in human cells. A subset of kinases, referred to as cyclin-dependent kinases (CDKs), are crucial regulators of eukaryotic cell cycle progression. In silico studies show high homology between mammalian CDK's and a group of CDK-like Plasmodium kinases including PfPK5 (Plasmodium falciparum protein kinase 5). Plasmodium homologues to CDK regulators, cyclins, have also been identified. Understanding the role of PfPK5 in cell cycle regulation would require analysis of subcellular localization and cell cycle-dependent expression. Immunofluorescence assays demonstrate that PfPK5 is localized in the nucleus. PfPK5's expression profile, as determined by western blotting, shows highest expression in the schizont stage, the stage when the atypical multiple nucleated form of the parasite is observed. Possible PfPK5 interacting partners were detected by performing an anti-PfPK5 immunoprecipitation assay. Additionally, a hemagglutinin (HA)-tagged PfPK5 construct was made to increase the sensitivity of immunoprecipitation assay and identification of PfPK5 interacting partners. The characterization of PfPK5 and its interacting partners may prove useful in identification of novel drug targets in the future.
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