Discovery of 7‑Methyl-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro‑1<i>H</i>‑indol-5-yl)‑7<i>H</i>‑pyrrolo[2,3‑<i>d</i>]pyrimidin-4-amine (GSK2606414), a Potent and Selective First-in-Class Inhibitor of Protein Kinase R (PKR)-like Endoplasmic Reticulum Kinase (PERK)

Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is activated in response to a variety of endoplasmic reticulum stresses implicated in numerous disease states. Evidence that PERK is implicated in tumorigenesis and cancer cell survival stimulated our search for small molecule inhibitors. Through screening and lead optimization using the human PERK crystal structure, we discovered compound <b>38</b> (GSK2606414), an orally available, potent, and selective PERK inhibitor. Compound <b>38</b> inhibits PERK activation in cells and inhibits the growth of a human tumor xenograft in mice

Discovery of Small Molecule RIP1 Kinase Inhibitors for the Treatment of Pathologies Associated with Necroptosis

Potent inhibitors of RIP1 kinase from three distinct series, 1-aminoisoquinolines, pyrrolo­[2,3-b]­pyridines, and furo­[2,3-d]­pyrimidines, all of the type II class recognizing a DLG-out inactive conformation, were identified from screening of our in-house kinase focused sets. An exemplar from the furo­[2,3-d]­pyrimidine series showed a dose proportional response in protection from hypothermia in a mouse model of TNFα induced lethal shock

Discovery of a Potent Boronic Acid Derived Inhibitor of the HCV RNA-Dependent RNA Polymerase

A boronic acid moiety was found to be a critical pharmacophore for enhanced in vitro potency against wild-type hepatitis C replicons and known clinical polymorphic and resistant HCV mutant replicons. The synthesis, optimization, and structure–activity relationships associated with inhibition of HCV replication in a subgenomic replication system for a series of non-nucleoside boron-containing HCV RNA-dependent RNA polymerase (NS5B) inhibitors are described. A summary of the discovery of <b>3</b> (GSK5852), a molecule which entered clinical trials in subjects infected with HCV in 2011, is included