{"title":"中等大小环肽的结构-活性关系,KRAS 抑制剂来自 mRNA 展示。","authors":"Mirai Kage, Ryuji Hayashi, Atsushi Matsuo, Minoru Tamiya, Shino Kuramoto, Kazuhiro Ohara, Machiko Irie, Aya Chiyoda, Koji Takano, Toshiya Ito, Tomoya Kotake, Ryuuichi Takeyama, Shiho Ishikawa, Kenichi Nomura, Noriyuki Furuichi, Yuya Morita, Satoshi Hashimoto, Hatsuo Kawada, Yoshikazu Nishimura, Keiji Nii, Takuya Shiraishi","doi":"10.1016/j.bmc.2024.117830","DOIUrl":null,"url":null,"abstract":"<div><p>Cyclic peptides are attracting attention as therapeutic agents due to their potential for oral absorption and easy access to tough intracellular targets. LUNA18, a clinical KRAS inhibitor, was transformed—without scaffold hopping—from the initial hit by using an mRNA display library that met our criteria for drug-likeness. In drug discovery using mRNA display libraries, hit compounds always possess a site linked to an mRNA tag. Here, we describe our examination of the Structure-Activity Relationship (SAR) using X-ray structures for chemical optimization near the site linked to the mRNA tag, equivalent to the <em>C</em>-terminus. Structural modifications near the <em>C</em>-terminus demonstrated a relatively wide range of tolerance for side chains. Furthermore, we show that a single atom modification is enough to change the pharmacokinetic (PK) profile. Since there are four positions where side chain modification is permissible in terms of activity, it is possible to flexibly adjust the pharmacokinetic profile by structurally optimizing the side chain. The side chain transformation findings demonstrated here may be generally applicable to hits obtained from mRNA display libraries.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":3.3000,"publicationDate":"2024-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Structure-activity relationships of middle-size cyclic peptides, KRAS inhibitors derived from an mRNA display\",\"authors\":\"Mirai Kage, Ryuji Hayashi, Atsushi Matsuo, Minoru Tamiya, Shino Kuramoto, Kazuhiro Ohara, Machiko Irie, Aya Chiyoda, Koji Takano, Toshiya Ito, Tomoya Kotake, Ryuuichi Takeyama, Shiho Ishikawa, Kenichi Nomura, Noriyuki Furuichi, Yuya Morita, Satoshi Hashimoto, Hatsuo Kawada, Yoshikazu Nishimura, Keiji Nii, Takuya Shiraishi\",\"doi\":\"10.1016/j.bmc.2024.117830\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>Cyclic peptides are attracting attention as therapeutic agents due to their potential for oral absorption and easy access to tough intracellular targets. LUNA18, a clinical KRAS inhibitor, was transformed—without scaffold hopping—from the initial hit by using an mRNA display library that met our criteria for drug-likeness. In drug discovery using mRNA display libraries, hit compounds always possess a site linked to an mRNA tag. Here, we describe our examination of the Structure-Activity Relationship (SAR) using X-ray structures for chemical optimization near the site linked to the mRNA tag, equivalent to the <em>C</em>-terminus. Structural modifications near the <em>C</em>-terminus demonstrated a relatively wide range of tolerance for side chains. Furthermore, we show that a single atom modification is enough to change the pharmacokinetic (PK) profile. Since there are four positions where side chain modification is permissible in terms of activity, it is possible to flexibly adjust the pharmacokinetic profile by structurally optimizing the side chain. The side chain transformation findings demonstrated here may be generally applicable to hits obtained from mRNA display libraries.</p></div>\",\"PeriodicalId\":255,\"journal\":{\"name\":\"Bioorganic & Medicinal Chemistry\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.3000,\"publicationDate\":\"2024-07-06\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Bioorganic & Medicinal Chemistry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S096808962400244X\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Bioorganic & Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S096808962400244X","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
环肽作为治疗药物备受关注,因为它们具有口服吸收的潜力,而且容易进入细胞内的强靶点。临床 KRAS 抑制剂 LUNA18 是利用符合我们药物相似性标准的 mRNA 展示文库从最初的命中化合物转化而来的,无需跳支架。在使用 mRNA 展示文库进行药物发现的过程中,命中化合物总是拥有一个与 mRNA 标记相连的位点。在此,我们介绍了利用 X 射线结构对结构-活性关系(SAR)进行的研究,以对与 mRNA 标记相连的位点(相当于 C 端)附近进行化学优化。C 端附近的结构修饰显示了侧链相对较宽的容许范围。此外,我们还表明,单个原子的修改就足以改变药代动力学(PK)曲线。由于在活性方面有四个位置允许侧链修饰,因此可以通过优化侧链结构来灵活调整药代动力学特征。本文所展示的侧链改造结果可能普遍适用于从 mRNA 展示文库中获得的命中物。
Structure-activity relationships of middle-size cyclic peptides, KRAS inhibitors derived from an mRNA display
Cyclic peptides are attracting attention as therapeutic agents due to their potential for oral absorption and easy access to tough intracellular targets. LUNA18, a clinical KRAS inhibitor, was transformed—without scaffold hopping—from the initial hit by using an mRNA display library that met our criteria for drug-likeness. In drug discovery using mRNA display libraries, hit compounds always possess a site linked to an mRNA tag. Here, we describe our examination of the Structure-Activity Relationship (SAR) using X-ray structures for chemical optimization near the site linked to the mRNA tag, equivalent to the C-terminus. Structural modifications near the C-terminus demonstrated a relatively wide range of tolerance for side chains. Furthermore, we show that a single atom modification is enough to change the pharmacokinetic (PK) profile. Since there are four positions where side chain modification is permissible in terms of activity, it is possible to flexibly adjust the pharmacokinetic profile by structurally optimizing the side chain. The side chain transformation findings demonstrated here may be generally applicable to hits obtained from mRNA display libraries.
期刊介绍:
Bioorganic & Medicinal Chemistry provides an international forum for the publication of full original research papers and critical reviews on molecular interactions in key biological targets such as receptors, channels, enzymes, nucleotides, lipids and saccharides.
The aim of the journal is to promote a better understanding at the molecular level of life processes, and living organisms, as well as the interaction of these with chemical agents. A special feature will be that colour illustrations will be reproduced at no charge to the author, provided that the Editor agrees that colour is essential to the information content of the illustration in question.