Discovery of GSK2656157: An Optimized PERK Inhibitor Selected for Preclinical Development
ACS Medicinal Chemistry Letters2013Vol. 4(10), pp. 964–968
Citations Over TimeTop 10% of 2013 papers
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 B. 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.
Related Papers
- → Detection and quantification of endoplasmic reticulum stress in living cells using the fluorescent compound, Thioflavin T(2013)128 cited
- → DIFFERENTIATION OF ENDOPLASMIC RETICULUM IN HEPATOCYTES(1971)276 cited
- → Morphology and function of the endoplasmic reticulum(1966)13 cited
- Endoplasmic Reticulum Stress and Liver Disease(2012)
- Endoplasmic reticulum stress and alcoholic liver disease(2009)