激酶
化学
蛋白酶体
背景(考古学)
蛋白质组
功能(生物学)
泛素
细胞生物学
磷脂酰肌醇
信号转导
计算生物学
生物化学
生物
基因
古生物学
作者
Wenzhi Ji,Eric S. Wang,Theresa D. Manz,Jie Jiang,Katherine A. Donovan,Xianmixinuer Abulaiti,Eric S. Fischer,Lewis C. Cantley,Tinghu Zhang,Nathanael S. Gray
标识
DOI:10.1016/j.ejmech.2022.115027
摘要
Phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks), a family of three members in mammals (α, β and γ), have emerged as potential therapeutic targets due to their role in regulating many important cellular signaling pathways. In comparison to the PI5P4Kα and PI5P4Kβ, which usually have similar expression profiles across cancer cells, PI5P4Kγ exhibits distinct expression patterns, and pathological functions for PI5P4Kγ have been proposed in the context of cancer and neurodegenerative diseases. PI5P4Kγ has very low kinase activity and has been proposed to inhibit the PI4P5Ks through scaffolding function, providing a rationale for developing a selective PI5P4Kγ degrader. Here, we report the development and characterization of JWZ-1-80, a first-in-class PI5P4Kγ degrader. JWZ-1-80 potently degrades PI5P4Kγ via the ubiquitin-proteasome system and exhibits proteome-wide selectivity and is therefore a useful tool compound for further dissecting the biological functions of PI5P4Kγ.
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