Synthesis and Anticancer Activity of Novel Actinonin Derivatives as HsPDF Inhibitors.,Journal of Medicinal Chemistry

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Synthesis and Anticancer Activity of Novel Actinonin Derivatives as HsPDF Inhibitors.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-06-18 , DOI: 10.1021/acs.jmedchem.0c00079
Liu Hu ₁ , Xing Cai ₂ , Suzhen Dong ₂ , Yongjia Zhen ₁ , Jidi Hu ₁ , Shenjun Wang ₁ , Jingwen Jiang ₁ , Jiawu Huang ₁ , Yuqiao Han ₂ , Yu Qian _{1,

3} , Yanqiu Yuan ₁ , Wenhao Hu _{1,

3}

Affiliation

Human mitochondrial peptide deformylase (HsPDF) is responsible for removing the formyl group from N-terminal formylmethionines of newly synthesized mitochondrial proteins and plays important roles in maintaining mitochondria function. It is overexpressed in various cancers and has been proposed as a novel therapeutic target. Actinonin, a naturally occurring peptidomimetic HsPDF inhibitor, was reported to inhibit the proliferation of a broad spectrum of human cancer cells in vitro. However, its efficacy and pharmacokinetic profile requires significant improvement for therapeutic purposes. To obtain HsPDF inhibitors as anticancer therapeutics, we screened an in-house collection of actinonin derivatives and found two initial hits with antiproliferation activity. Further optimization along the peptidomimetic backbone lead to two series of compounds containing substituted phenyl moieties. They are potent HsPDF inhibitors and exhibited greatly improved antiproliferation activity in selected cancer cell lines. Finally, compound 15m significantly inhibited the growth of human colon cancer in xenograft animal models.

中文翻译：

新型肌动蛋白衍生物作为HsPDF抑制剂的合成及其抗癌活性。

人线粒体肽去甲酰基化酶（HsPDF）负责从新合成的线粒体蛋白的N末端甲酰基甲硫氨酸中去除甲酰基，并在维持线粒体功能中发挥重要作用。它在各种癌症中过表达，并已被提议作为一种新型治疗靶标。肌动蛋白是一种天然的拟肽HsPDF抑制剂，据报道在体外能抑制多种人类癌细胞的增殖。但是，其功效和药代动力学特性需要显着改善以达到治疗目的。为了获得作为抗癌治疗剂的HsPDF抑制剂，我们筛选了肌动蛋白衍生物的内部集合，并发现了两个具有抗增殖活性的初始产物。沿拟肽骨架的进一步优化导致包含取代的苯基部分的两个系列的化合物。它们是有效的HsPDF抑制剂，在选定的癌细胞系中表现出极大的抗增殖活性。最后，复合15m在异种移植动物模型中显着抑制了人类结肠癌的生长。

更新日期：2020-07-09

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