Hamada Keisuke, Omura Noriko, Taguchi Akihiro, Baradaran-Heravi Alireza, Kotake Masaya, Arai Misaki, Takayama Kentaro, Taniguchi Atsuhiko, Roberge Michel, Hayashi Yoshio
Department of Medicinal Chemistry, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
ACS Med Chem Lett. 2019 Sep 23;10(10):1450-1456. doi: 10.1021/acsmedchemlett.9b00273. eCollection 2019 Oct 10.
We report a novel negamycin derivative TCP-1109 () which serves as a potent readthrough drug candidate against nonsense-associated diseases. We previously demonstrated that TCP-112 (), a nor-compound of native 3--deoxynegmaycin, showed a higher readthrough activity than (+)-negamycin. In the present study, we performed a structure-activity relationship (SAR) study of compound focused on its 3-amino group in an effort to develop a more potent readthrough compound. Introduction of a variety of natural or unnatural amino acids to the 3-amino group gave us the more potent derivative which has about four times higher readthrough activity than in a cell-based assay using a premature termination codon of TGA derived from Duchenne muscular dystrophy. The activity was dose-dependent and relatively selective for TGA. However, the activities for TAG and TAA were also higher than those of (+)-negamycin and . Moreover, compound showed significant cell-based readthrough activity for several nonsense mutations derived from other nonsense-associated diseases. It is suggested that has the potential to be a readthrough drug useful for the treatment of many kinds of nonsense-associated diseases.
我们报道了一种新型的_negamycin_衍生物TCP-1109（），它是一种针对无义相关疾病的强效通读药物候选物。我们之前证明，天然3-脱氧_negamycin_的去甲化合物TCP-112（）显示出比（+）-negamycin更高的通读活性。在本研究中，我们对化合物进行了构效关系（SAR）研究，重点关注其3-氨基，以开发一种更有效的通读化合物。在3-氨基上引入各种天然或非天然氨基酸，得到了更有效的衍生物，在使用来自杜氏肌营养不良症的TGA提前终止密码子的基于细胞的测定中，其通读活性比高出约四倍。该活性是剂量依赖性的，并且对TGA具有相对选择性。然而，对TAG和TAA的活性也高于（+）-negamycin和。此外，化合物对源自其他无义相关疾病的几种无义突变显示出显著的基于细胞的通读活性。提示有潜力成为一种可用于治疗多种无义相关疾病的通读药物。
