State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
J Med Chem. 2024 Sep 12;67(17):15328-15352. doi: 10.1021/acs.jmedchem.4c00798. Epub 2024 Aug 22.
Based on the founding member of imipridones, , a class of dehydrogenated imipridone derivatives was designed, synthesized, and evaluated in a series of biochemical and biological assays as human caseinolytic protease P (hClpP) activators. Mechanism studies for one of the most potent compounds, , indicated that it can potently bind to both recombinant and cellular hClpP, effectively promote the formation of hClpP tetradecamer, efficiently induce the degradation of hClpP substrates, robustly upregulate the expression of ATF4, and strongly inhibit the phosphorylations of AKT and ERK. More importantly, exhibited a promising pharmacokinetic profile in rats and could penetrate the blood brain barrier. It showed highly potent antitumor activity in a MIAPACA2 cell line derived pancreatic cancer model in BALB/c nude mice.
基于 imipridones 的创始成员，设计、合成了一类脱氢 imipridone 衍生物，并在一系列生化和生物学测定中作为人组织蛋白酶 P (hClpP) 激活剂进行了评估。对其中一种活性最强的化合物进行的机制研究表明，它可以与重组和细胞 hClpP 强力结合，有效地促进 hClpP 十四聚体的形成，高效诱导 hClpP 底物的降解，显著上调 ATF4 的表达，并强烈抑制 AKT 和 ERK 的磷酸化。更重要的是， 在大鼠中表现出有前景的药代动力学特征，并能够穿透血脑屏障。它在 BALB/c 裸鼠衍生的 MIAPACA2 细胞系胰腺癌模型中表现出很强的抗肿瘤活性。
