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中型循环的结构-活性关系,KRAS抑制剂来自mRNA显示器

Mirai Kage¹, Ryuji Hayashi¹, Atsushi Matsuo¹

¹Research Division, Chugai Pharmaceutical Co. Ltd., 216, Totsuka-cho, Totsuka-ku, Yokohama, Kanagawa 244-8602, Japan.

Bioorganic & medicinal chemistry

|July 9, 2024

概括

循环LUNA18,一个KRAS抑制剂,使用mRNA显示进行了优化. 在mRNA标签部位附近的化学修饰允许灵活调整药物类似性质和药理动力学.

科学领域:

药用化学医学化学
药物发现药物发现药物发现
结构生物学结构生物学

背景情况:

循环因口服吸收和细胞内向目标访问而显示出有前途的治疗药物.
LUNA18,一种KRAS抑制剂,是从使用mRNA显示技术的初步成功开发出来的.
来自mRNA显示库的命中化合物与mRNA标签联系在一起.

研究的目的:

调查LUNA18.的结构与活动关系 (SAR).
通过化学修改与mRNA标签 (C端) 相关的区域来优化LUNA18.
探索结构修改对药理动力学 (PK) 概况的影响.

主要方法:

利用X射线晶体学指导化学优化.
在LUNA18.18上进行了结构-活动关系 (SAR) 研究.
研究C端的修改,相当于mRNA标记部位.

主要成果:

在C端附近的结构修改显示了对各种侧链的耐受性.
一个单个原子的修改足以改变药理动力学 (PK) 概况.
确定了四个允许的修改站点,用于基于活动的优化.
通过侧链优化灵活调整药物动力学概况.

结论:

在mRNA标签部位附近的化学修饰可以灵活优化循环类候选药物.
侧链修改提供了一种多功能策略来调整药理动力学特性.
这些发现可能适用于利用mRNA显示库的其他药物发现工作.

关键词:

这是一种循环.这是一种KRAS抑制剂.月亮18月18日月亮中等大小的分子分子.口服可生物利用的.在mRNA显示库中显示mRNA图书馆.

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