Discovery of Small Molecule RIP1 Kinase Inhibitors for the Treatment of Pathologies Associated with Necroptosis
Discovery of Small Molecule RIP1 Kinase Inhibitors for the Treatment of Pathologies Associated with Necroptosis
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DOI：
10.1021/ml400382p
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发表时间：
2013-12-01
影响因子：
4.2
通讯作者：
Gough, Peter J.
中科院分区：
文献类型：
--
作者：
Harris, Philip A.;Bandyopadhyay, Deepak;Gough, Peter J.
来自三个不同系列的有效的RIP1激酶抑制剂，1-氨基异喹啉，吡咯[2，3-b]吡啶和呋喃[2，3-d]嘧啶，都是识别DLG-OUT非活性构象的II类化合物，从我们的内部激酶集中集的筛选中被鉴定出来。在肿瘤坏死因子α诱导的致死性休克的小鼠模型中，呋喃并[2，3-d]嘧啶系列的样本在低温保护方面显示出剂量成比例的反应。
Potent inhibitors of RIP1 kinase from three distinct series, 1-aminoisoquinolines, pyrrolo[2,3-b]pyridines, and furo[2,3-d]pyrimidines, all of the type II class recognizing a DLG-out inactive conformation, were identified from screening of our in-house kinase focused sets. An exemplar from the furo[2,3-d]pyrimidine series showed a dose proportional response in protection from hypothermia in a mouse model of TNF alpha induced lethal shock.