Development of novel imipridone derivatives with potent anti-cancer activities as human caseinolytic peptidase P (hClpP) activators

IF 4.5 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Bioorganic Chemistry Pub Date : 2024-08-30 DOI:10.1016/j.bioorg.2024.107765

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Abstract

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 EC₅₀ value of 0.24 µM and inhibited the growth of the three cancer cell lines with IC₅₀ 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.

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作为人类酪蛋白溶肽酶 P (hClpP) 激活剂开发具有强效抗癌活性的新型亚胺吡啶酮衍生物。

以临床阶段的小分子 hClpP 激活剂 ONC201 为基础，设计并合成了一类亚胺培酮衍生物。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。结果发现，与 ONC201 相比，一些化合物能更有效地激活 hClpP，并更有效地抑制三种癌细胞株的细胞生长。最有效的化合物 ZYZ-17 激活 hClpP 的 EC50 值为 0.24 µM，抑制三种癌细胞株生长的 IC50 值小于 10 nM。对 ZYZ-17 的机理研究表明，它能有效激活细胞中的 hClpP，高效诱导 hClpP 底物降解，并能强力诱导三种癌细胞株凋亡。此外，ZYZ-17 还显示出良好的药代动力学（PK）特征，并在 BALB/c 裸鼠胰腺癌 MIA PACA-2 异种移植模型中表现出极强的体内抗肿瘤活性。

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来源期刊

Bioorganic Chemistry 生物-生化与分子生物学

CiteScore

9.70

自引率

3.90%

发文量

679

审稿时长

31 days

期刊介绍： Bioorganic Chemistry publishes research that addresses biological questions at the molecular level, using organic chemistry and principles of physical organic chemistry. The scope of the journal covers a range of topics at the organic chemistry-biology interface, including: enzyme catalysis, biotransformation and enzyme inhibition; nucleic acids chemistry; medicinal chemistry; natural product chemistry, natural product synthesis and natural product biosynthesis; antimicrobial agents; lipid and peptide chemistry; biophysical chemistry; biological probes; bio-orthogonal chemistry and biomimetic chemistry. For manuscripts dealing with synthetic bioactive compounds, the Journal requires that the molecular target of the compounds described must be known, and must be demonstrated experimentally in the manuscript. For studies involving natural products, if the molecular target is unknown, some data beyond simple cell-based toxicity studies to provide insight into the mechanism of action is required. Studies supported by molecular docking are welcome, but must be supported by experimental data. The Journal does not consider manuscripts that are purely theoretical or computational in nature. The Journal publishes regular articles, short communications and reviews. Reviews are normally invited by Editors or Editorial Board members. Authors of unsolicited reviews should first contact an Editor or Editorial Board member to determine whether the proposed article is within the scope of the Journal.