Discovery of GSK2656157: An Optimized PERK Inhibitor Selected for Preclinical Development

作者：Jeffrey M. Axten, Stuart P. Romeril, Arthur Y. L. Shu, Jeffrey M. Ralph, Jesús R. Medina, Yanhong Feng, William Hoi Hong Li, Seth W. Grant, Dirk A. Heerding, Elisabeth A. Minthorn, Thomas Mencken, Nathan Gaul, Aaron S. Goetz, Thomas Blaine Stanley, Annie M. Hassell, Robert T. Gampe, Charity L. Atkins, Rakesh Kumar · 发表于：ACS Medicinal Chemistry Letters · 年份：2013 · DOI：10.1021/ml400228e · 被引用次数：241 · 研究领域：Endoplasmic Reticulum Stress and Disease、Autophagy in Disease and Therapy、Ubiquitin and proteasome pathways

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.