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

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.

SUBMITTER: Wood SD 

PROVIDER: S-EPMC5733266 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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

Wood Spencer D SD   Grant Wayne W   Adrados Isabel I   Choi Jun Yong JY   Alburger James M JM   Duckett Derek R DR   Roush William R WR  

ACS medicinal chemistry letters 20171122 12

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 (IC<sub>50</sub> < 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 UL  ...[more]

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