Discovery and structure activity relationship of the first potent cryptosporidium FIKK kinase inhibitor.
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.
Structural Genomics Consortium, Toronto M5G1L7, Canada; Molecular Genetics, University of Toronto, Toronto M5S 1A8, Canada.
Khan T
KT
Osman
Department of Chemistry, University of Toronto, Toronto M5S 3H6, Canada.
Juntao
J
Ye
Department of Chemistry, University of Toronto, Toronto M5S 3H6, Canada; China Pharmaceutical University, Jiangsu Sheng 210009, China.
Zhihao
Z
Shi
Department of Chemistry, University of Toronto, Toronto M5S 3H6, Canada.
Christina
C
Toker
Structural Genomics Consortium, Toronto M5G1L7, Canada.
Diogo
D
Lovato
Department of Medicine, Cellular, Molecular, and Biomedical Sciences Program, University of Vermont, Burlington 05405, USA.
Rajiv S
RS
Jumani
UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 2759, USA.
William
W
Zuercher
Department of Medicine, Cellular, Molecular, and Biomedical Sciences Program, University of Vermont, Burlington 05405, USA.
Christopher D
CD
Huston
Structural Genomics Consortium, Toronto M5G1L7, Canada.
Aled M
AM
Edwards
Department of Chemistry, University of Toronto, Toronto M5S 3H6, Canada.
Mark
M
Lautens
Structural Genomics Consortium, Toronto M5G1L7, Canada. Electronic address: santha.santhakumar@utoronto.ca.
Vijayaratnam
V
Santhakumar
Structural Genomics Consortium, Toronto M5G1L7, Canada.
Raymond
R
Hui
D000595:Amino Acid Sequence; D003458:Cryptosporidium / Q000201:enzymology* / Q000254:growth & development; D055808:Drug Discovery; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011494:Protein Kinases / Q000737:chemistry*; D017386:Sequence Homology, Amino Acid; D013057:Spectrum Analysis / Q000379:methods; D013329:Structure-Activity Relationship
D047428:Protein Kinase Inhibitors; D011494:Protein Kinases
Cryptosporidium; FIKK Kinase inhibitor; Kinase inhibitor