Protein kinases are important regulators of cell proliferation, migration, and differentiation. Cancer cells of many types over-express protein kinases. Drugs that inhibit specific protein kinases are now used to treat some human cancers. Anti-parasite drug discovery receives almost no support from the pharmaceutical industry, because the clients for the drugs are poor. """"""""Alternative Use"""""""" drug discovery, which involves testing of drugs approved for control of non-parasitic diseases as treatment for parasite infections is a cost-effective and fast route for finding new lead compounds that may be studied further as anti-parasite drugs. Novel drugs are needed for treatment of human African trypanosomiasis, which is caused by the protozoan parasite Trypanosoma brucei. Our preliminary bioinformatic and pharmacological studies indicate that some protein kinases are important for viability and may be targeted for drug discovery in T. brucei.
In Specific Aim 1, we will perform a """"""""focused screen"""""""" of drugs that inhibit protein kinases to find out which of them kill blood stream form T. brucei in culture. Promising anti-trypanosome lead compounds will be evaluated further in a mouse model of T. brucei infection.
In Specific Aim 2, we will validate the target of the protein kinase inhibitors, using a combination of affinity chromatography/chemical proteomics and molecular genetics approaches. Data from these exploratory/developmental (R21) studies will provide new lead compounds for anti-trypanosome drug discovery, and form the basis for a future work to delineate the biological relevance of protein kinase signaling in T. brucei.
Trypanosomes cause diseases that affect millions of people world-wide. Work described in this proposal may lead to discovery of new drugs for treatment of human African trypanosomiasis.
| Woodring, Jennifer L; Patel, Gautam; Erath, Jessey et al. (2015) EVALUATION OF AROMATIC 6-SUBSTITUTED THIENOPYRIMIDINES AS SCAFFOLDS AGAINST PARASITES THAT CAUSE TRYPANOSOMIASIS, LEISHMANIASIS, AND MALARIA. Medchemcomm 6:339-346 |
| Behera, Ranjan; Thomas, Sarah M; Mensa-Wilmot, Kojo (2014) New chemical scaffolds for human african trypanosomiasis lead discovery from a screen of tyrosine kinase inhibitor drugs. Antimicrob Agents Chemother 58:2202-10 |
| Katiyar, Samiksha; Kufareva, Irina; Behera, Ranjan et al. (2013) Lapatinib-binding protein kinases in the African trypanosome: identification of cellular targets for kinase-directed chemical scaffolds. PLoS One 8:e56150 |
| Patel, Gautam; Karver, Caitlin E; Behera, Ranjan et al. (2013) Kinase scaffold repurposing for neglected disease drug discovery: discovery of an efficacious, lapatinib-derived lead compound for trypanosomiasis. J Med Chem 56:3820-32 |
