化学
威罗菲尼
高通量筛选
小分子
荧光
脚手架
肝再生
化学生物学
生物化学
激酶
蛋白激酶A
亲缘关系
组合化学
计算生物学
细胞生物学
再生(生物学)
癌症研究
转移性黑色素瘤
黑色素瘤
生物医学工程
物理
生物
医学
量子力学
作者
Theresa Kircher,Tatu Pantsar,Andreas Oder,Jens Peter von Kries,Michael Juchum,Bent Pfaffenrot,Philip Kloevekorn,Wolfgang Albrecht,Roland Selig,Stefan Laufer
标识
DOI:10.1016/j.ejmech.2020.112901
摘要
The mitogen-activated protein kinase kinase 4 (MKK4) plays a key role in liver regeneration and is under investigation as a target for stimulating hepatocytes to increased proliferation. Therefore, new small molecules inhibiting MKK4 may represent a promising approach for treating acute and chronic liver diseases. Fluorescently labeled compounds are useful tools for high-throughput screenings of large compound libraries. Here we utilized the azaindole-based scaffold of FDA-approved BRAF inhibitor vemurafenib 1, which displays off-target activity on MKK4, as a starting point in our fluorescent compound design. Chemical variation of the scaffold and optimization led to a selection of fluorescent 5-TAMRA derivatives which possess high binding affinities on MKK4. Compound 45 represents a suitable tool compound for Fluorescence polarization assays to identify new small-molecule inhibitors of MKK4.
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