In Silico HTS and Structure Based Optimization of Indazole-Derived ULK1 Inhibitors

  • ACS Med Chem Lett. 2017 Nov 22;8(12):1258-1263. doi: 10.1021/acsmedchemlett.7b00344.
Spencer D Wood  1 ,  Wayne Grant  1 ,  Isabel Adrados  1 ,  Jun Yong Choi  1 ,  James M Alburger  1 ,  Derek R Duckett  1 ,  William R Roush  1
Affiliations
  • 1. Department of Chemistry and Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458, United States.
PMID: 29259744 DOI: 10.1021/acsmedchemlett.7b00344
Abstract

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.

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