2. Academic Validation
  3. Discovery of GSK2656157: An Optimized PERK Inhibitor Selected for Preclinical Development

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

  • ACS Med Chem Lett. 2013 Aug 12;4(10):964-8. doi: 10.1021/ml400228e.
Jeffrey M Axten 1,  Stuart P Romeril 1,  Arthur Shu 1,  Jeffrey Ralph 1,  Jesús R Medina 1,  Yanhong Feng 1,  William Hoi Hong Li 1,  Seth W Grant 1,  Dirk A Heerding 1,  Elisabeth Minthorn 1,  Thomas Mencken 1,  Nathan Gaul 2,  Aaron Goetz 3,  Thomas Stanley 3,  Annie M Hassell 4,  Robert T Gampe 4,  Charity Atkins 1,  Rakesh Kumar 1
Affiliations

Affiliations

  • 1 Oncology Research, Protein Dynamics DPU, GlaxoSmithKline Research and Development , Collegeville, Pennsylvania 19426, United States.
  • 2 Screening and Compound Profiling, GlaxoSmithKline Research and Development , Collegeville, Pennsylvania 19426, United States.
  • 3 Screening and Compound Profiling, GlaxoSmithKline Research and Development , Research Triangle Park, North Carolina 27713, United States.
  • 4 Biomolecular Structure, Computational and Structural Chemistry, GlaxoSmithKline Research and Development , Research Triangle Park, North Carolina 27709, United States.
PMID: 24900593 DOI: 10.1021/ml400228e
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.

Keywords

PERK; UPR; fluorine interaction; kinase; lead optimization; structure−activity relationship.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-153160
    99.82%, PERK Inhibitor