School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China.
J Med Chem. 2020 Jul 9;63(13):6959-6978. doi: 10.1021/acs.jmedchem.0c00079. Epub 2020 Jun 26.
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 significantly inhibited the growth of human colon cancer in xenograft animal models.
人线粒体肽脱甲酰基酶（HsPDF）负责从新合成的线粒体蛋白的 N 端甲酰甲硫氨酸上去除甲酰基，在维持线粒体功能方面发挥着重要作用。它在各种癌症中过度表达，并被提议作为一种新的治疗靶点。放线菌素酮，一种天然存在的肽拟态 HsPDF 抑制剂，据报道可在体外抑制广泛的人类癌细胞的增殖。然而，其疗效和药代动力学特征需要显著改善才能用于治疗目的。为了获得 HsPDF 抑制剂作为抗癌治疗药物，我们筛选了放线菌素酮的内部化合物库，发现了两种具有增殖抑制活性的初始先导化合物。进一步沿肽拟态骨架优化得到了含有取代苯基部分的两个系列化合物。它们是有效的 HsPDF 抑制剂，并在选定的癌细胞系中表现出大大提高的增殖抑制活性。最后，化合物 显著抑制了异种移植动物模型中人类结肠癌的生长。
