HiberCell Inc. 619 West 54th Street, New York, NY 10019, USA.
AMRI, 26 Corporate Circle, Albany, NY 12203, USA.
Bioorg Med Chem Lett. 2021 Jul 1;43:128058. doi: 10.1016/j.bmcl.2021.128058. Epub 2021 Apr 23.
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.
蛋白激酶 R（PKR）样内质网激酶（PERK）是未折叠蛋白反应（UPR）的三种内质网（ER）跨膜传感器之一，可调节蛋白质合成，减轻细胞 ER 应激，并与肿瘤发生和延长癌细胞存活有关。在这项研究中，我们报告了一系列 2-氨基-3-酰胺-5-芳基吡啶，这些化合物被鉴定为有效的、选择性的和口服生物可利用的 PERK 抑制剂。在所研究的系列化合物中，化合物（28）a（R）-2-氨基-5-（4-（2-（3,5-二氟苯基）-2-羟基乙酰胺基）-2-乙基苯基）-N-异丙基烟酰胺具有很强的生化和细胞活性，在小鼠中具有良好的药代动力学和 70%的口服生物利用度。鉴于这些数据，我们在 786-O 肾癌细胞癌异种移植模型中研究了这种化合物（28）。我们观察到剂量依赖性的、统计学上显著的肿瘤生长抑制，支持使用这种工具化合物进行进一步的机制研究。
