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

Matthew A Hulverson; Ryan Choi; Samuel L M Arnold; Deborah A Schaefer; Andrew Hemphill; Molly C McCloskey; Dana P Betzer; Joachim Müller; Rama S R Vidadala; Grant R Whitman; Kasey L Rivas; Lynn K Barrett; Robert C Hackman; Melissa S Love; Case W McNamara; Thomas K Shaughnessy; Alison Kondratiuk; Matthew Kurnick; Patricia N Banfor; James J Lynch; Gail M Freiberg; Dale J Kempf; Dustin J Maly; Michael W Riggs; Kayode K Ojo; Wesley C Van Voorhis

doi:10.1016/j.ijpara.2017.08.006

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.

Authors

Matthew A Hulverson¹, Ryan Choi¹, Samuel L M Arnold¹, Deborah A Schaefer², Andrew Hemphill³, Molly C McCloskey¹, Dana P Betzer², Joachim Müller³, Rama S R Vidadala⁴, Grant R Whitman¹, Kasey L Rivas¹, Lynn K Barrett¹, Robert C Hackman⁵, Melissa S Love⁶, Case W McNamara⁶, Thomas K Shaughnessy⁷, Alison Kondratiuk⁷, Matthew Kurnick⁷, Patricia N Banfor⁷, James J Lynch⁷, Gail M Freiberg⁷, Dale J Kempf⁷, Dustin J Maly⁸, Michael W Riggs², Kayode K Ojo⁹, Wesley C Van Voorhis¹⁰

Affiliations

¹ Department of Medicine, Division of Allergy and Infectious Disease, Center for Emerging and Reemerging Infectious Disease (CERID), University of Washington, Seattle, WA 98109, USA.
² School of Animal and Comparative Biomedical Sciences, College of Agriculture and Life Sciences, University of Arizona, Tucson, AZ 85721, USA.
³ Institute of Parasitology, Vetsuisse Faculty, University of Bern, Länggass-Strasse 122, CH-3012 Bern, Switzerland.
⁴ Department of Chemistry, University of Washington, Seattle, WA 98195, USA.
⁵ Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Department of Pathology, University of Washington, Seattle, WA 98195, USA; Department of Laboratory Medicine, University of Washington, Seattle, WA 98195, USA.
⁶ California Institute for Biomedical Research, La Jolla, CA, USA.
⁷ Research and Development, AbbVie, Inc, North Chicago, IL 60064, USA.
⁸ Department of Chemistry, University of Washington, Seattle, WA 98195, USA; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
⁹ Department of Medicine, Division of Allergy and Infectious Disease, Center for Emerging and Reemerging Infectious Disease (CERID), University of Washington, Seattle, WA 98109, USA. Electronic address: ojo67kk@u.washington.edu.
¹⁰ Department of Medicine, Division of Allergy and Infectious Disease, Center for Emerging and Reemerging Infectious Disease (CERID), University of Washington, Seattle, WA 98109, USA. Electronic address: wesley@uw.edu.

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding