<i>In Silico</i> HTS and Structure Based Optimization of Indazole-Derived ULK1 Inhibitors

Abstract

We present the outcome of an <i>in silico</i> high throughput screen (HTS) and optimization of a small molecule Unc-51-Like Kinase 1 (ULK1) inhibitor hit, <b>SR-17398</b>, 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 (<b>3a</b> and <b>3g</b>) 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.