title: Pyrimidine-based tricyclic molecules as potent and orally efficacious inhibitors of wee1 kinase.
abstract: 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 K i 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.
authors.affiliation: Cancer Research, Molecular Modeling, Pharmacology, and High Throughput Biology, Research and Development, AbbVie , 1 North Waukegan Road, North Chicago, Illinois 60064-6114, United States.
authors.forename: Yunsong
authors.initials: Y
authors.lastname: Tong
authors.affiliation: Cancer Research, Molecular Modeling, Pharmacology, and High Throughput Biology, Research and Development, AbbVie , 1 North Waukegan Road, North Chicago, Illinois 60064-6114, United States.
authors.forename: Maricel
authors.initials: M
authors.lastname: Torrent
authors.affiliation: Cancer Research, Molecular Modeling, Pharmacology, and High Throughput Biology, Research and Development, AbbVie , 1 North Waukegan Road, North Chicago, Illinois 60064-6114, United States.
authors.forename: Alan S
authors.initials: AS
authors.lastname: Florjancic
authors.affiliation: Cancer Research, Molecular Modeling, Pharmacology, and High Throughput Biology, Research and Development, AbbVie , 1 North Waukegan Road, North Chicago, Illinois 60064-6114, United States.
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Bromberg
authors.affiliation: Cancer Research, Molecular Modeling, Pharmacology, and High Throughput Biology, Research and Development, AbbVie , 1 North Waukegan Road, North Chicago, Illinois 60064-6114, United States.
authors.forename: Fritz G
authors.initials: FG
authors.lastname: Buchanan
authors.affiliation: Cancer Research, Molecular Modeling, Pharmacology, and High Throughput Biology, Research and Development, AbbVie , 1 North Waukegan Road, North Chicago, Illinois 60064-6114, United States.
authors.forename: Debra C
authors.initials: DC
authors.lastname: Ferguson
authors.affiliation: Cancer Research, Molecular Modeling, Pharmacology, and High Throughput Biology, Research and Development, AbbVie , 1 North Waukegan Road, North Chicago, Illinois 60064-6114, United States.
authors.forename: Eric F
authors.initials: EF
authors.lastname: Johnson
authors.affiliation: Cancer Research, Molecular Modeling, Pharmacology, and High Throughput Biology, Research and Development, AbbVie , 1 North Waukegan Road, North Chicago, Illinois 60064-6114, United States.
authors.forename: Loren M
authors.initials: LM
authors.lastname: Lasko
authors.affiliation: Cancer Research, Molecular Modeling, Pharmacology, and High Throughput Biology, Research and Development, AbbVie , 1 North Waukegan Road, North Chicago, Illinois 60064-6114, United States.
authors.forename: David
authors.initials: D
authors.lastname: Maag
authors.affiliation: Cancer Research, Molecular Modeling, Pharmacology, and High Throughput Biology, Research and Development, AbbVie , 1 North Waukegan Road, North Chicago, Illinois 60064-6114, United States.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Merta
authors.affiliation: Cancer Research, Molecular Modeling, Pharmacology, and High Throughput Biology, Research and Development, AbbVie , 1 North Waukegan Road, North Chicago, Illinois 60064-6114, United States.
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Olson
authors.affiliation: Cancer Research, Molecular Modeling, Pharmacology, and High Throughput Biology, Research and Development, AbbVie , 1 North Waukegan Road, North Chicago, Illinois 60064-6114, United States.
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Osterling
authors.affiliation: Cancer Research, Molecular Modeling, Pharmacology, and High Throughput Biology, Research and Development, AbbVie , 1 North Waukegan Road, North Chicago, Illinois 60064-6114, United States.
authors.forename: Nirupama
authors.initials: N
authors.lastname: Soni
authors.affiliation: Cancer Research, Molecular Modeling, Pharmacology, and High Throughput Biology, Research and Development, AbbVie , 1 North Waukegan Road, North Chicago, Illinois 60064-6114, United States.
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Shoemaker
authors.affiliation: Cancer Research, Molecular Modeling, Pharmacology, and High Throughput Biology, Research and Development, AbbVie , 1 North Waukegan Road, North Chicago, Illinois 60064-6114, United States.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Penning
keywords: Wee1 kinase inhibitors; antitumor