Pyrimidine-Based Tricyclic Molecules as Potent and Orally Efficacious Inhibitors of Wee1 Kinase

被引：20

作者：

Tong, Yunsong ^{[1
]}

Torrent, Maricel ^{[2
]}

Florjancic, Alan S. ^{[1
]}

Bromberg, Kenneth D. ^{[1
]}

Buchanan, Fritz G. ^{[1
]}

Ferguson, Debra C. ^{[1
]}

Johnson, Eric F. ^{[1
]}

Lasko, Loren M. ^{[1
]}

Maag, David ^{[1
]}

Merta, Philip J. ^{[4
]}

Olson, Amanda M. ^{[3
]}

Osterling, Donald J. ^{[3
]}

Soni, Nirupama ^{[1
]}

Shoemaker, Alexander R. ^{[1
]}

Penning, Thomas D. ^{[1
]}

机构：

[1] AbbVie, Canc Res, N Chicago, IL 60064 USA

[2] AbbVie, Mol Modeling, N Chicago, IL 60064 USA

[3] AbbVie, Pharmacol, N Chicago, IL 60064 USA

[4] AbbVie, Res & Dev, High Throughput Biol, N Chicago, IL 60064 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2015年 / 6卷 / 01期

关键词：

Wee1 kinase inhibitors; antitumor; CHECKPOINT KINASE; MITOTIC CATASTROPHE; TYROSINE KINASE; GENE-EXPRESSION; CANCER-THERAPY; CDK1;

D O I：

10.1021/ml5002745

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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-mu 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.

引用

页码：58 / 62

页数：5

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