以亚咪啶酮的创始成员 ONC201 为基础，设计、合成了一类脱氢亚咪啶酮衍生物，并通过一系列生化和生物学测定对其作为人酪蛋白分解蛋白酶 P (hClpP) 激活剂进行了评估。对最有效的化合物之一 XT6 的机制研究表明，它可以有效地结合重组和细胞 hClpP，有效促进 hClpP 四聚体的形成，有效诱导 hClpP 底物的降解，强力上调 ATF4 的表达，并强烈抑制 AKT 和 ERK 的磷酸化。更重要的是，XT6 在大鼠中表现出良好的药代动力学特征，并且可以穿透血脑屏障。它在 MIAPACA2 细胞系衍生的 BALB/c 裸鼠胰腺癌模型中显示出高效的体内抗肿瘤活性。

Based on the founding member of imipridones, ONC201, 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, XT6, 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, XT6 exhibited a promising pharmacokinetic profile in rats and could penetrate the blood brain barrier. It showed highly potent in vivo antitumor activity in a MIAPACA2 cell line derived pancreatic cancer model in BALB/c nude mice.