Bumped Kinase Inhibitors as therapy for apicomplexan parasitic diseases: lessons learned

Ryan Choi; Matthew A Hulverson; Wenlin Huang; Rama S R Vidadala; Grant R Whitman; Lynn K Barrett; Deborah A Schaefer; Dana P Betzer; Michael W Riggs; J Stone Doggett; Andrew Hemphill; Luis Miguel Ortega-Mora; Molly C McCloskey; Samuel L M Arnold; Robert C Hackman; Kennan C Marsh; James J Lynch; Gail M Freiberg; Bruce E Leroy; Dale J Kempf; Robert K M Choy; Eugenio L de Hostos; Dustin J Maly; Erkang Fan; Kayode K Ojo; Wesley C Van Voorhis

doi:10.1016/j.ijpara.2020.01.006

Bumped Kinase Inhibitors as therapy for apicomplexan parasitic diseases: lessons learned

Int J Parasitol. 2020 May;50(5):413-422. doi: 10.1016/j.ijpara.2020.01.006. Epub 2020 Mar 26.

Authors

Ryan Choi¹, Matthew A Hulverson¹, Wenlin Huang², Rama S R Vidadala³, Grant R Whitman¹, Lynn K Barrett¹, Deborah A Schaefer⁴, Dana P Betzer⁴, Michael W Riggs⁴, J Stone Doggett⁵, Andrew Hemphill⁶, Luis Miguel Ortega-Mora⁷, Molly C McCloskey¹, Samuel L M Arnold¹, Robert C Hackman⁸, Kennan C Marsh⁹, James J Lynch⁹, Gail M Freiberg⁹, Bruce E Leroy⁹, Dale J Kempf⁹, Robert K M Choy¹⁰, Eugenio L de Hostos¹⁰, Dustin J Maly³, Erkang Fan², Kayode K Ojo¹, Wesley C Van Voorhis¹¹

Affiliations

¹ Department of Medicine, Division of Allergy and Infectious Diseases, Center for Emerging and Reemerging Infectious Diseases (CERID), University of Washington, Seattle, WA 98109, USA.
² Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
³ Department of Chemistry, University of Washington, Seattle, WA 98195, USA.
⁴ School of Animal and Comparative Biomedical Sciences, College of Agriculture and Life Sciences, University of Arizona, Tucson, AZ 85721, USA.
⁵ VA Portland Health Care System, Portland, OR 97239, USA.
⁶ Institute of Parasitology, Vetsuisse Faculty, University of Bern, Länggass-Strasse 122, CH-3012 Bern, Switzerland.
⁷ SALUVET, Animal Health Department, Faulty of Veterinary Sciences, Complutense University of Madrid, Madrid, Spain.
⁸ 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.
⁹ Research and Development, AbbVie, Inc, North Chicago, IL 60064, USA.
¹⁰ PATH, San Francisco, CA 94108 USA.
¹¹ Department of Medicine, Division of Allergy and Infectious Diseases, Center for Emerging and Reemerging Infectious Diseases (CERID), University of Washington, Seattle, WA 98109, USA. Electronic address: wesley@uw.edu.

Abstract

Bumped Kinase Inhibitors, targeting Calcium-dependent Protein Kinase 1 in apicomplexan parasites with a glycine gatekeeper, are promising new therapeutics for apicomplexan diseases. Here we will review advances, as well as challenges and lessons learned regarding efficacy, safety, and pharmacology that have shaped our selection of pre-clinical candidates.

Keywords: Apicomplexa; Bumped Kinase Inhibitor; Calcium-dependent Protein Kinases; Cryptosporidium; Gatekeeper; Neospora; Sarcocystis; Toxoplasma.

Publication types

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

MeSH terms

Animals
Apicomplexa / drug effects*
Apicomplexa / metabolism
Coccidiosis / drug therapy*
Cryptosporidiosis / drug therapy
Cryptosporidium / drug effects
Cryptosporidium / metabolism
Humans
Protein Kinase Inhibitors* / adverse effects
Protein Kinase Inhibitors* / chemistry
Protein Kinase Inhibitors* / pharmacology
Protein Kinases / drug effects
Protein Kinases / metabolism
Toxoplasma / drug effects
Toxoplasma / metabolism
Toxoplasmosis / drug therapy

Substances

Protein Kinase Inhibitors
Protein Kinases
calcium-dependent protein kinase

Abstract

Publication types

MeSH terms

Substances

Grants and funding