Zhang Yanzhi, Jiang Jinxin, Ding Hao, Li Qiannan, Xiao Yibei, Sun Haiying
Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
Bioorg Chem. 2024 Dec;153:107765. doi: 10.1016/j.bioorg.2024.107765. Epub 2024 Aug 30.
Based on a clinically staged small molecular hClpP activator ONC201, a class of imipridone derivatives was designed and synthesized. These compounds were evaluated in a protease hydrolytic assay, as well as cell growth inhibition assays in three cancer cell lines, MIA PACA-2, HCT116, and MV4-11. A number of compounds that can more potently activate hClpP and more effectively inhibit cell growth in the three cancer cell lines than ONC201 were identified. The most potent compound, ZYZ-17, activated hClpP with an EC value of 0.24 µM and inhibited the growth of the three cancer cell lines with IC values of less than 10 nM. Mechanism studies for ZYZ-17 revealed that it potently activates cellular hClpP, efficiently induces the degradation of hClpP substrates, and robustly induces apoptosis in the three cancer cell lines. Furthermore, ZYZ-17 demonstrated a promising pharmacokinetic (PK) profile and exhibited highly potent in vivo antitumor activity in a pancreatic cancer MIA PACA-2 xenograft model in BALB/c nude mice.
基于临床分期的小分子hClpP激活剂ONC201，设计并合成了一类咪吡啶酮衍生物。这些化合物在蛋白酶水解试验以及三种癌细胞系MIA PACA - 2、HCT116和MV4 - 11的细胞生长抑制试验中进行了评估。鉴定出了一些比ONC201更能有效激活hClpP且更能有效抑制这三种癌细胞系细胞生长的化合物。最有效的化合物ZYZ - 17激活hClpP的EC值为0.24 μM，抑制这三种癌细胞系生长的IC值小于10 nM。对ZYZ - 17的机制研究表明，它能有效激活细胞内的hClpP，高效诱导hClpP底物的降解，并在这三种癌细胞系中强烈诱导细胞凋亡。此外，ZYZ - 17显示出良好的药代动力学（PK）特性，并在BALB/c裸鼠的胰腺癌MIA PACA - 2异种移植模型中表现出高效的体内抗肿瘤活性。
