基于高通量筛选和结构的吲唑衍生的ULK1抑制剂优化
HTS and Structure Based Optimization of Indazole-Derived ULK1 Inhibitors.
作者信息
Wood Spencer D, Grant Wayne, Adrados Isabel, Choi Jun Yong, Alburger James M, Duckett Derek R, Roush William R
机构信息
Department of Chemistry and Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458, United States.
出版信息
ACS Med Chem Lett. 2017 Nov 22;8(12):1258-1263. doi: 10.1021/acsmedchemlett.7b00344. eCollection 2017 Dec 14.
Abstract
We present the outcome of an high throughput screen (HTS) and optimization of a small molecule Unc-51-Like Kinase 1 (ULK1) inhibitor hit, , with an indazole core. Docking studies guided design efforts that led to inhibitors with increased activity vs ULK1 (IC < 50 nM). The most advanced molecules in this inhibitor series ( and ) hold promise for further development into selective ULK1 molecular probes to interrogate the biology of ULK1 and to assess whether selectively targeting autophagy is an effective anticancer strategy.
摘要
我们展示了一种高通量筛选（HTS）的结果以及对一种具有吲唑核心的小分子Unc-51样激酶1（ULK1）抑制剂命中物的优化。对接研究指导了设计工作，从而得到了对ULK1活性增强的抑制剂（IC<50 nM）。该抑制剂系列中最先进的分子（和）有望进一步开发成选择性ULK1分子探针，以探究ULK1的生物学特性，并评估选择性靶向自噬是否是一种有效的抗癌策略。
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