Discovery and structure of a new inhibitor scaffold of the autophagy initiating kinase ULK1.
Discovery and structure of a new inhibitor scaffold of the autophagy initiating kinase ULK1.
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DOI：
10.1016/j.bmc.2015.07.034
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发表时间：
2015-09-01
影响因子：
3.5
通讯作者：
Shokat KM
中科院分区：
文献类型：
--
作者：
Lazarus MB;Shokat KM
真核细胞的能量稳态是一个复杂而基本的过程，在多种人类疾病中受到错误调节。能量调节的一个关键组成部分是一个称为自噬的过程，涉及细胞成分的回收。近年来，研究自噬的机制以了解一个重要的细胞过程并评估靶向自噬的治疗潜力引起了人们的极大兴趣。被称为ULK1的激酶的激活通过驱动下游通路来启动自噬，所述下游通路导致围绕待降解的细胞内容物的双膜结合囊泡的形成。在这里，我们报告了ULK1抑制剂的发现，该抑制剂具有改进的选择性和与激酶结合的化合物的高分辨率晶体结构，这将是研究细胞自噬的有用工具。
Energy homeostasis in eukaryotic cells is a complex and fundamental process that is misregulated in several human diseases. A key component of energy regulation is a process called autophagy that involves the recycling of cellular components. There has been much recent interest in studying the mechanism of autophagy to understand an important cellular process and to evaluate therapeutic potential in targeting autophagy. Activation of a kinase called ULK1 initiates autophagy by driving downstream pathways that lead to the formation of double membrane bound vesicles that surround the cellular contents that are to be degraded. Here, we report the discovery of an inhibitor of ULK1 with improved selectivity and a high-resolution crystal structure of the compound bound to the kinase, which will be useful tools for studying autophagy in cells.