Discovery and Structure Activity Relationship of the First Potent Cryptosporidium FIKK Kinase Inhibitor

Publication date: Available online 24 January 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Khan T. Osman, Juntao Ye, Zhihao Shi, Christina Toker, Diogo Lovato, Rajiv S. Jumani, William Zuercher, Christopher D. Huston, Aled M Edwards, Mark Lautens, Vijayaratnam Santhakumar, Raymond Hui
FIKKs are parasite-specific protein kinases with distinctive sequence motifs and their biological roles have not been completely elucidated. Here, we report the first potent Cryptosporidium FIKK (CpFIKK) inhibitor. We identified 4b as a potent (IC50=0.2 nM) inhibitor of CpFIKK catalytic activity. In addition, we identified both CpCDPK1 selective as well as dually acting CpFIKK-CDPK1 inhibitors from the same structural class of compounds. We evaluated these CpFIKK inhibitors for inhibition of parasite growth in vitro. The observed effects on parasite growth did not correlate with CpFIKK inhibition, suggesting that CpFIKK may not be involved in parasite growth.

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