Discovery of Inhibitor of Wnt Production 2 (IWP-2) and Related Compounds As Selective ATP-Competitive Inhibitors of Casein Kinase 1 (CK1) δ/ε,Journal of Medicinal Chemistry

当前位置： X-MOL 学术 › J. Med. Chem. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Discovery of Inhibitor of Wnt Production 2 (IWP-2) and Related Compounds As Selective ATP-Competitive Inhibitors of Casein Kinase 1 (CK1) δ/ε
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-04-09 00:00:00 , DOI: 10.1021/acs.jmedchem.8b00095
Balbina García-Reyes ₁ , Lydia Witt ₂ , Björn Jansen ₂ , Ebru Karasu ₁ , Tanja Gehring ₁ , Johann Leban ₃ , Doris Henne-Bruns ₁ , Christian Pichlo ₄ , Elena Brunstein ₄ , Ulrich Baumann ₄ , Fabian Wesseler ₅ , Bernd Rathmer ₅ , Dennis Schade _{5,

6} , Christian Peifer ₂ , Uwe Knippschild ₁

Affiliation

Inhibitors of Wnt production (IWPs) are known antagonists of the Wnt pathway, targeting the membrane-bound O-acyltransferase porcupine (Porcn) and thus preventing a crucial Wnt ligand palmitoylation. Since IWPs show structural similarities to benzimidazole-based CK1 inhibitors, we hypothesized that IWPs could also inhibit CK1 isoforms. Molecular modeling revealed a plausible binding mode of IWP-2 in the ATP binding pocket of CK1δ which was confirmed by X-ray analysis. In vitro kinase assays demonstrated IWPs to be ATP-competitive inhibitors of ^wtCK1δ. IWPs also strongly inhibited the gatekeeper mutant ^M82FCK1δ. When profiled in a panel of 320 kinases, IWP-2 specifically inhibited CK1δ. IWP-2 and IWP-4 also inhibited the viability of various cancer cell lines. By a medicinal chemistry approach, we developed improved IWP-derived CK1 inhibitors. Our results suggest that the effects of IWPs are not limited to Porcn, but also might influence CK1δ/ε-related pathways.

中文翻译：

发现Wnt产生2（IWP-2）和相关化合物的抑制剂作为酪蛋白激酶1（CK1）δ/ε的ATP竞争性抑制剂

Wnt产生的抑制剂（IWPs）是Wnt途径的已知拮抗剂，其靶向膜结合的O-酰基转移酶豪猪（Porcn），从而防止关键的Wnt配体棕榈酰化。由于IWP显示出与基于苯并咪唑的CK1抑制剂的结构相似性，因此我们假设IWP也可以抑制CK1异构体。分子模型揭示了在CK1δ的ATP结合口袋中IWP-2的合理结合模式，这通过X射线分析得以证实。体外证明激酶测定IWPs是的ATP竞争性抑制剂^重量CK1δ。IWP也强烈抑制了Gatekeeper突变体^M82FCK1δ。当在一组320种激酶中进行分析时，IWP-2特异性抑制CK1δ。IWP-2和IWP-4还抑制了各种癌细胞系的生存能力。通过药物化学方法，我们开发了改良的IWP衍生的CK1抑制剂。我们的结果表明，IWP的作用不仅限于Porcn，还可能影响CK1δ/ε相关途径。

更新日期：2018-04-09

点击分享查看原文

点击收藏

阅读更多本刊最新论文本刊介绍/投稿指南11