Discovery of GSK2656157: An Optimized PERK Inhibitor Selected for Preclinical DevelopmentClick to copy article linkArticle link copied!
- Jeffrey M. Axten
- Stuart P. Romeril
- Arthur Shu
- Jeffrey Ralph
- Jesús R. Medina
- Yanhong Feng
- William Hoi Hong Li
- Seth W. Grant
- Dirk A. Heerding
- Elisabeth Minthorn
- Thomas Mencken
- Nathan Gaul
- Aaron Goetz
- Thomas Stanley
- Annie M. Hassell
- Robert T. Gampe
- Charity Atkins
- Rakesh Kumar
Abstract
We recently reported the discovery of GSK2606414 (1), a selective first in class inhibitor of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), which inhibited PERK activation in cells and demonstrated tumor growth inhibition in a human tumor xenograft in mice. In continuation of our drug discovery program, we applied a strategy to decrease inhibitor lipophilicity as a means to improve physical properties and pharmacokinetics. This report describes our medicinal chemistry optimization culminating in the discovery of the PERK inhibitor GSK2656157 (6), which was selected for advancement to preclinical development.
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