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Bioorg Med Chem. 2017 Mar 1;25(5):1672-1680. doi: 10.1016/j.bmc.2017.01.036. Epub 2017 Jan 24.

Discovery and structure activity relationship of the first potent cryptosporidium FIKK kinase inhibitor.

Author information

1
Structural Genomics Consortium, Toronto M5G1L7, Canada; Molecular Genetics, University of Toronto, Toronto M5S 1A8, Canada.
2
Department of Chemistry, University of Toronto, Toronto M5S 3H6, Canada.
3
Department of Chemistry, University of Toronto, Toronto M5S 3H6, Canada; China Pharmaceutical University, Jiangsu Sheng 210009, China.
4
Structural Genomics Consortium, Toronto M5G1L7, Canada.
5
Department of Medicine, Cellular, Molecular, and Biomedical Sciences Program, University of Vermont, Burlington 05405, USA.
6
UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 2759, USA.
7
Structural Genomics Consortium, Toronto M5G1L7, Canada. Electronic address: santha.santhakumar@utoronto.ca.

Abstract

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=0.2nM) 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.

KEYWORDS:

Cryptosporidium; FIKK Kinase inhibitor; Kinase inhibitor

PMID:
28162900
DOI:
10.1016/j.bmc.2017.01.036
[Indexed for MEDLINE]

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