4G34

Crystal Structure of GSK6924 Bound to PERK (R587-R1092, delete A660-T867) at 2.70 A Resolution

Summary for 4G34

• Entry DOI: 10.2210/pdb4g34/pdb
• Related: 3QD2 4G31
• Descriptor: Eukaryotic translation initiation factor 2-alpha kinase 3, 1-[5-(4-aminothieno[3,2-c]pyridin-3-yl)-2,3-dihydro-1H-indol-1-yl]-2-phenylethanone (3 entities in total)
• Functional Keywords: deletion mutant, catalytic domain, synthetic inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human); More
• Cellular location: Endoplasmic reticulum membrane; Single-pass type I membrane protein: Q9NZJ5
• Total number of polymer chains: 1
• Total formula weight: 35182.70

Authors

Gampe, R.T.,Axten, J.M. (deposition date: 2012-07-13, release date: 2012-08-08, Last modification date: 2023-09-13)

Primary citation

Axten, J.M.,Medina, J.R.,Feng, Y.,Shu, A.,Romeril, S.P.,Grant, S.W.,Li, W.H.,Heerding, D.A.,Minthorn, E.,Mencken, T.,Atkins, C.,Liu, Q.,Rabindran, S.,Kumar, R.,Hong, X.,Goetz, A.,Stanley, T.,Taylor, J.D.,Sigethy, S.D.,Tomberlin, G.H.,Hassell, A.M.,Kahler, K.M.,Shewchuk, L.M.,Gampe, R.T.
Discovery of 7-Methyl-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (GSK2606414), a Potent and Selective First-in-Class Inhibitor of Protein Kinase R (PKR)-like Endoplasmic Reticulum Kinase (PERK).
J.Med.Chem., 55:7193-7207, 2012

PubMed Abstract: 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 38 (GSK2606414), an orally available, potent, and selective PERK inhibitor. Compound 38 inhibits PERK activation in cells and inhibits the growth of a human tumor xenograft in mice.

PubMed: 22827572
DOI: 10.1021/jm300713s

Experimental method

X-RAY DIFFRACTION (2.7 Å)