Potent and selective inhibitors of CDPK1 fromT. gondiiandC. parvumbased on a 5-aminopyrazole-4-carboxamide scaffold.
5-Aminopyrazole-4-carboxamide was used as an alternative scaffold to substitute for the pyrazolopyrimidine of a known "bumped kinase inhibitor" to create selective inhibitors of calcium-dependent protein kinase-1 from bothToxoplasma gondiiandCryptosporidium parvum. Compounds with low nanomolar inhibitory potencies against the target enzymes were obtained. The most selective inhibitors also exhibited submicromolar activities inT. gondiicell proliferation assays and were shown to be non-toxic to mammalian cells.
Department of Biochemistry, University of Washington, Seattle, WA 98195, United States.
Zhongsheng
Z
Zhang
Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle, WA 98195, United States.
Kayode K
KK
Ojo
Department of Chemistry, University of Washington, Seattle, WA 98195, United States.
Ramasubbarao
R
Vidadala
Department of Biochemistry, University of Washington, Seattle, WA 98195, United States.
Wenlin
W
Huang
Seattle Biomedical Research Institute, Seattle, WA 98109, United States.
Jennifer A
JA
Geiger
Seattle Biomedical Research Institute, Seattle, WA 98109, United States.
Suzanne
S
Scheele
Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle, WA 98195, United States.
Ryan
R
Choi
Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle, WA 98195, United States.
Molly C
MC
Reid
Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle, WA 98195, United States.
Katelyn R
KR
Keyloun
Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle, WA 98195, United States.
Kasey
K
Rivas
Department of Biochemistry, University of Washington, Seattle, WA 98195, United States.
Latha Kallur
LK
Siddaramaiah
High Throughput Biology, Global Pharmaceutical R&D, AbbVie, North Chicago, IL 60064, United States.
Kenneth M
KM
Comess
High Throughput Biology, Global Pharmaceutical R&D, AbbVie, North Chicago, IL 60064, United States.
Kenneth P
KP
Robinson
High Throughput Biology, Global Pharmaceutical R&D, AbbVie, North Chicago, IL 60064, United States.
Philip J
PJ
Merta
High Throughput Biology, Global Pharmaceutical R&D, AbbVie, North Chicago, IL 60064, United States.
Lemma
L
Kifle
Department of Biochemistry, University of Washington, Seattle, WA 98195, United States.
Wim G J
WG
Hol
Seattle Biomedical Research Institute, Seattle, WA 98109, United States.
Marilyn
M
Parsons
Department of Biochemistry, University of Washington, Seattle, WA 98195, United States.
Ethan A
EA
Merritt
Department of Chemistry, University of Washington, Seattle, WA 98195, United States.
Dustin J
DJ
Maly
Department of Biochemistry, University of Washington, Seattle, WA 98195, United States.
Christophe L M J
CL
Verlinde
Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle, WA 98195, United States.
Wesley C
WC
Van Voorhis
Department of Biochemistry, University of Washington, Seattle, WA 98195, United States.
Erkang
E
Fan
Calcium-dependent protein kinase-1; Cryptosporidium parvum; Enzyme inhibitor; Selectivity; Toxoplasma gondii