Advances in bumped kinase inhibitors for human and animal therapy for cryptosporidiosis

Int J Parasitol. 2017 Oct;47(12):753-763. doi: 10.1016/j.ijpara.2017.08.006. Epub 2017 Sep 9.

Abstract

Improvements have been made to the safety and efficacy of bumped kinase inhibitors, and they are advancing toward human and animal use for treatment of cryptosporidiosis. As the understanding of bumped kinase inhibitor pharmacodynamics for cryptosporidiosis therapy has increased, it has become clear that better compounds for efficacy do not necessarily require substantial systemic exposure. We now have a bumped kinase inhibitor with reduced systemic exposure, acceptable safety parameters, and efficacy in both the mouse and newborn calf models of cryptosporidiosis. Potential cardiotoxicity is the limiting safety parameter to monitor for this bumped kinase inhibitor. This compound is a promising pre-clinical lead for cryptosporidiosis therapy in animals and humans.

Keywords: BKI 1369; Calcium-dependent protein kinase 1; Cryptosporidiosis; Drug target; Gatekeeper residue.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Administration, Oral
  • Animals
  • Animals, Newborn
  • Cattle
  • Cryptosporidiosis / drug therapy*
  • Cryptosporidium parvum / drug effects*
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Female
  • Heart / drug effects
  • Humans
  • Inhibitory Concentration 50
  • Interferon-gamma / genetics
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Mutagenicity Tests
  • Pregnancy
  • Protein Binding
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / blood
  • Protein Kinase Inhibitors / therapeutic use*
  • Protein Kinase Inhibitors / toxicity
  • Safety

Substances

  • Protein Kinase Inhibitors
  • Interferon-gamma