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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-2IWP-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
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