7MF0

Co-crystal structure of PERK with inhibitor (R)-2-amino-N-cyclopropyl-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)nicotinamide

This is a non-PDB format compatible entry.

Summary for 7MF0

• Entry DOI: 10.2210/pdb7mf0/pdb
• Descriptor: Eukaryotic translation initiation factor 2-alpha kinase 3,Eukaryotic translation initiation factor 2-alpha kinase 3, 2-amino-N-cyclopropyl-5-(4-{[(2R)-2-(3,5-difluorophenyl)-2-hydroxyacetyl]amino}-2-methylphenyl)pyridine-3-carboxamide (2 entities in total)
• Functional Keywords: kinase, perk, inhibitor, hc5469, transferase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 1
• Total formula weight: 37268.82

Authors

Wiens, B.,Koszelak-Rosenblum, M.,Surman, M.D.,Zhu, G.,Mulvihill, M.J. (deposition date: 2021-04-08, release date: 2021-05-19, Last modification date: 2023-10-18)

Primary citation

Calvo, V.,Surguladze, D.,Li, A.H.,Surman, M.D.,Malibhatla, S.,Bandaru, M.,Jonnalagadda, S.K.,Adarasandi, R.,Velmala, M.,Singireddi, D.R.P.,Velpuri, M.,Nareddy, B.R.,Sastry, V.,Mandati, C.,Guguloth, R.,Siddiqui, S.,Patil, B.S.,Chad, E.,Wolfley, J.,Gasparek, J.,Feldman, K.,Betzenhauser, M.,Wiens, B.,Koszelak-Rosenblum, M.,Zhu, G.,Du, H.,Rigby, A.C.,Mulvihill, M.J.
Discovery of 2-amino-3-amido-5-aryl-pyridines as highly potent, orally bioavailable, and efficacious PERK kinase inhibitors.
Bioorg.Med.Chem.Lett., 43:128058-128058, 2021

PubMed Abstract: The 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-isopropylnicotinamide 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.

PubMed: 33895276
DOI: 10.1016/j.bmcl.2021.128058

Experimental method

X-RAY DIFFRACTION (2.809 Å)