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PDBsum entry 4tzr
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References listed in PDB file
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Key reference
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Title
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Development of an orally available and central nervous system (cns) penetrant toxoplasma gondii calcium-Dependent protein kinase 1 (tgcdpk1) inhibitor with minimal human ether-A-Go-Go-Related gene (herg) activity for the treatment of toxoplasmosis.
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Authors
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R.S.Vidadala,
K.L.Rivas,
K.K.Ojo,
M.A.Hulverson,
J.A.Zambriski,
I.Bruzual,
T.L.Schultz,
W.Huang,
Z.Zhang,
S.Scheele,
A.E.Derocher,
R.Choi,
L.K.Barrett,
L.K.Siddaramaiah,
W.G.Hol,
E.Fan,
E.A.Merritt,
M.Parsons,
G.Freiberg,
K.Marsh,
D.J.Kempf,
V.B.Carruthers,
N.Isoherranen,
J.S.Doggett,
W.C.Van voorhis,
D.J.Maly.
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Ref.
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J Med Chem, 2016,
59,
6531-6546.
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PubMed id
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Abstract
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New therapies are needed for the treatment of toxoplasmosis, which is a disease
caused by the protozoan parasite Toxoplasma gondii. To this end, we previously
developed a potent and selective inhibitor (compound 1) of Toxoplasma gondii
calcium-dependent protein kinase 1 (TgCDPK1) that possesses antitoxoplasmosis
activity in vitro and in vivo. Unfortunately, 1 has potent human
ether-a-go-go-related gene (hERG) inhibitory activity, associated with long Q-T
syndrome, and consequently presents a cardiotoxicity risk. Here, we describe the
identification of an optimized TgCDPK1 inhibitor 32, which does not have a hERG
liability and possesses a favorable pharmacokinetic profile in small and large
animals. 32 is CNS-penetrant and highly effective in acute and latent mouse
models of T. gondii infection, significantly reducing the amount of parasite in
the brain, spleen, and peritoneal fluid and reducing brain cysts by >85%.
These properties make 32 a promising lead for the development of a new
antitoxoplasmosis therapy.
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Secondary reference #1
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Title
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Toxoplasma gondii calcium-Dependent protein kinase 1 is a target for selective kinase inhibitors.
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Authors
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K.K.Ojo,
E.T.Larson,
K.R.Keyloun,
L.J.Castaneda,
A.E.Derocher,
K.K.Inampudi,
J.E.Kim,
T.L.Arakaki,
R.C.Murphy,
L.Zhang,
A.J.Napuli,
D.J.Maly,
C.L.Verlinde,
F.S.Buckner,
M.Parsons,
W.G.Hol,
E.A.Merritt,
W.C.Van voorhis.
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Ref.
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Nat Struct Biol, 2010,
17,
602-607.
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PubMed id
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Secondary reference #2
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Title
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Multiple determinants for selective inhibition of apicomplexan calcium-Dependent protein kinase cdpk1.
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Authors
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E.T.Larson,
K.K.Ojo,
R.C.Murphy,
S.M.Johnson,
Z.Zhang,
J.E.Kim,
D.J.Leibly,
A.M.Fox,
M.C.Reid,
E.J.Dale,
B.G.Perera,
J.Kim,
S.N.Hewitt,
W.G.Hol,
C.L.Verlinde,
E.Fan,
W.C.Van voorhis,
D.J.Maly,
E.A.Merritt.
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Ref.
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J Med Chem, 2012,
55,
2803-2810.
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PubMed id
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