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Torrent M.,Molecular Modeling | Merta P.J.,High Throughput Biology | Olson A.M.,Pharmacology | Osterling D.J.,Pharmacology
ACS Medicinal Chemistry Letters | Year: 2014

Aided by molecular modeling, compounds with a pyrimidine-based tricyclic scaffold were designed and confirmed to inhibit Wee1 kinase. Structure-activity studies identified key pharmacophores at the aminoaryl and halo-benzene regions responsible for binding affinity with sub-nM Ki values. The potent inhibitors demonstrated sub-μM activities in both functional and mechanism-based cellular assays and also possessed desirable pharmacokinetic profiles. The lead molecule, 31, showed oral efficacy in potentiating the antiproliferative activity of irinotecan, a cytotoxic agent, in a NCI-H1299 mouse xenograft model. © 2014 American Chemical Society.


Zhang Z.,University of Washington | Ojo K.K.,University of Washington | Vidadala R.,University of Washington | Huang W.,University of Washington | And 18 more authors.
ACS Medicinal Chemistry Letters | Year: 2014

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 both Toxoplasma gondii and Cryptosporidium parvum. Compounds with low nanomolar inhibitory potencies against the target enzymes were obtained. The most selective inhibitors also exhibited submicromolar activities in T. gondii cell proliferation assays and were shown to be nontoxic to mammalian cells. © 2013 American Chemical Society.


PubMed | High Throughput Biology, Seattle Biomedical Research Institute and University of Washington
Type: Journal Article | Journal: ACS medicinal chemistry letters | Year: 2014

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 both

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