7mf0
From Proteopedia
Co-crystal structure of PERK with inhibitor (R)-2-amino-N-cyclopropyl-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)nicotinamide
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 the three endoplasmic reticulum (ER) transmembrane sensors of the unfolded protein response (UPR) that regulates protein synthesis, alleviates cellular ER stress and has been implicated in tumorigenesis and prolonged cancer cell survival. In this study, we report a series of 2-amino-3-amido-5-aryl-pyridines that we have identified as potent, selective, and orally bioavailable PERK inhibitors. Amongst the series studied herein, compound (28) a (R)-2-Amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-ethylphenyl)-N-iso propylnicotinamide has demonstrated potent biochemical and cellular activity, robust pharmacokinetics and 70% oral bioavailability in mice. Given these data, this compound (28) was studied in the 786-O renal cell carcinoma xenograft model. We observed dose-dependent, statistically significant tumor growth inhibition, supporting the use of this tool compound in additional mechanistic studies. Discovery of 2-amino-3-amido-5-aryl-pyridines as highly potent, orally bioavailable, and efficacious PERK kinase inhibitors.,Calvo V, Surguladze D, Li AH, Surman MD, Malibhatla S, Bandaru M, Jonnalagadda SK, Adarasandi R, Velmala M, Singireddi DRP, Velpuri M, Nareddy BR, Sastry V, Mandati C, Guguloth R, Siddiqui S, Patil BS, Chad E, Wolfley J, Gasparek J, Feldman K, Betzenhauser M, Wiens B, Koszelak-Rosenblum M, Zhu G, Du H, Rigby AC, Mulvihill MJ Bioorg Med Chem Lett. 2021 Apr 23;43:128058. doi: 10.1016/j.bmcl.2021.128058. PMID:33895276[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||||
