We present the outcome of an in silico high throughput screen (HTS) and optimization of a small molecule Unc-51-Like Kinase 1 (ULK1) inhibitor hit, SR-17398, with an indazole core. Docking studies guided design efforts that led to inhibitors with increased activity vs ULK1 (IC₅₀ < 50 nM). The most advanced molecules in this inhibitor series (3a and 3g) 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.

中文翻译：

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In silico HTS和基于吲哚的ULK1抑制剂的结构优化

我们介绍了一个计算机高通量筛选（HTS）的结果，并优化了带有吲唑核的小分子Unc-51-like激酶1（ULK1）抑制剂命中的SR-17398。对接研究指导了设计工作，这些工作导致抑制剂相对于ULK1具有更高的活性（IC ₅₀ <50 nM）。该抑制剂系列中最先进的分子（3a和3g）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有效的抗癌策略。