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

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.

PMID: 32224121
PMCID: PMC8565993
DOI: 10.1016/j.ijpara.2020.01.006

Review

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

Ryan Choi et al. Int J Parasitol. 2020 May.

. 2020 May;50(5):413-422.

doi: 10.1016/j.ijpara.2020.01.006. Epub 2020 Mar 26.

Authors

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.

PMID: 32224121
PMCID: PMC8565993
DOI: 10.1016/j.ijpara.2020.01.006

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.

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Conflict of interest statement

Conflict of Interest: WCVV is an owner/officer of ParaTheraTech Inc, a company which is seeking to bring bumped kinase inhibitors to the animal health market.

Figures

**Fig. 1.**
Central scaffolds of lead bumped kinase inhibitors (BKIs). BKI development and testing was centered around three main scaffolds: pyrrolopyrimidines (PrP), pyrazolopyrimidines (PP), and 5-aminopyrazole-4-carboxamides (AC).

**Fig. 2.**
Substituents of chiral and non-chiral Bumped Kinase Inhibitors (BKIs). (A) BKI-1634’s R2 substituent contains a chiral oxolane ring. Modifying this to a six-membered oxane ring results in a loss of chirality. (B) BKIs-1712, -1713, -1768, and -1769 possess a chiral 4-hydroxybutan-2-yl R2 substituent. Addition of a methyl group to form the 4-hydroxy-2-methylbutan-2-yl substituent resolves chirality.

See this image and copyright information in PMC

References

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

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

Authors

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Abstract

Conflict of interest statement

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