期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 43, 期 -, 页码 -出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2021.128058
关键词
PERK; UPR; Kinase; Inhibitor; Orally bioavailable; 786-O cell; Efficacy; Cancer; Structure-activity-relationships (SAR)
资金
- Advanced Photon Source beam line GMCACAT
- Federal funds from the NCI, National Institutes of Health [ACB-12002]
- NIGMS, National Institutes of Health [AGM-12006]
- DOE Office of Science by Argonne National Laboratory [DE-AC02-06CH11357]
In this study, a series of potent, selective, and orally bioavailable PERK inhibitors were identified, with compound (28) showing robust pharmacokinetics and significant tumor growth inhibition in a renal cell carcinoma xenograft model. This compound warrants further investigation as a tool compound for mechanistic studies.
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-(3,5difluorophenyl)-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 dosedependent, statistically significant tumor growth inhibition, supporting the use of this tool compound in additional mechanistic studies.
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