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Pyrimidine-based tricyclic molecules as potent and orally efficacious inhibitors of wee1 kinase
Yunsong Tong1, Maricel Torrent1, Alan S Florjancic1
1Cancer Research, Molecular Modeling, Pharmacology, and High Throughput Biology, Research and Development, AbbVie , 1 North Waukegan Road, North Chicago, Illinois 60064-6114, United States.
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.
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