8eq9
Co-crystal structure of PERK with compound 11
Structural highlights
DiseaseE2AK3_HUMAN Wolcott-Rallison syndrome. The disease is caused by mutations affecting the gene represented in this entry.[1] FunctionE2AK3_HUMAN Phosphorylates the alpha subunit of eukaryotic translation-initiation factor 2 (EIF2), leading to its inactivation and thus to a rapid reduction of translational initiation and repression of global protein synthesis. Serves as a critical effector of unfolded protein response (UPR)-induced G1 growth arrest due to the loss of cyclin-D1 (CCND1) (By similarity). Publication Abstract from PubMedThe protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is one of three endoplasmic reticulum (ER) transmembrane sensors of the unfolded protein response (UPR) responsible for regulating protein synthesis and alleviating ER stress. PERK has been implicated in tumorigenesis, cancer cell survival as well metabolic diseases such as diabetes. The structure-based design and optimization of a novel mandelamide-derived pyrrolopyrimidine series of PERK inhibitors as described herein, resulted in the identification of compound 26, a potent, selective, and orally bioavailable compound suitable for interrogating PERK pathway biology in vitro and in vivo, with pharmacokinetics suitable for once-a-day oral dosing in mice. Optimization of a Novel Mandelamide-Derived Pyrrolopyrimidine Series of PERK Inhibitors.,Stokes ME, Surman MD, Calvo V, Surguladze D, Li AH, Gasparek J, Betzenhauser M, Zhu G, Du H, Rigby AC, Mulvihill MJ Pharmaceutics. 2022 Oct 19;14(10):2233. doi: 10.3390/pharmaceutics14102233. PMID:36297668[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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