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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-?M 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.

SUBMITTER: Tong Y

PROVIDER: S-EPMC4291713 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Pyrimidine-based tricyclic molecules as potent and orally efficacious inhibitors of wee1 kinase.

Tong Yunsong Y Torrent Maricel M Florjancic Alan S AS Bromberg Kenneth D KD Buchanan Fritz G FG Ferguson Debra C DC Johnson Eric F EF Lasko Loren M LM Maag David D Merta Philip J PJ Olson Amanda M AM Osterling Donald J DJ Soni Nirupama N Shoemaker Alexander R AR Penning Thomas D TD

ACS medicinal chemistry letters 20140806 1

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 ...[more]

PMID: 25589931

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