Journal
PHARMACEUTICS
Volume 14, Issue 10, Pages -Publisher
MDPI
DOI: 10.3390/pharmaceutics14102233
Keywords
ER stress; PERK; UPR; kinase; inhibitor; cancer; diabetes; small molecule; structure-activity-relationship (SAR)
Categories
Funding
- Industrial Macromolecular Crystallography Association
- Hauptman-Woodward Medical Research Institute
- NCI, National Institutes of Health [ACB-12002]
- NIGMS, National Institutes of Health [AGM-12006]
- DOE Office of Science [DE-AC02-06CH11357]
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This study presents the design and optimization of a novel PERK inhibitor that can effectively block the PERK pathway, showing potential applications in anti-tumor and anti-diabetes therapy.
The 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.
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