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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Cryptosporidium / enzymology*
  • Cryptosporidium / growth & development
  • Drug Discovery
  • Humans
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinases / chemistry*
  • Sequence Homology, Amino Acid
  • Spectrum Analysis / methods
  • Structure-Activity Relationship

Substances

  • Protein Kinase Inhibitors
  • Protein Kinases