减少性C(sp2) -C(sp3) 合协议,使得Cereblon E3-Ligase BRD4蛋白解-向奇默体的链接器探索成为可能
Kaitlyn Lovato1, Danielle Loskot1, Christine Gelin1
1Discovery Chemistry, Therapeutics Discovery, Johnson & Johnson, 3210 Merryfield RowLa Jolla, San Diego, California 92121, United States.
Journal of medicinal chemistry
|May 9, 2025
概括
新的PROTACs (蛋白质分解向嵌合体) 使用基连接用于CRBN结合剂,改善细胞透性和选择性. 这种方法增强了对具有挑战性的疾病目标的药物发现.
科学领域:
- 药用化学 医学化学
- 药物发现 药物发现 药物发现
- 化学生物学 化学生物学
背景情况:
- 针对蛋白质分解的仿真体 (PROTACs) 提供了一种新的治疗策略,用于针对传统抑制剂难以处理的蛋白质.
- 目前的 PROTAC 主要使用 E3 结合酶cereblon (CRBN) 来利用无素-蛋白酶体系统进行蛋白质降解.
研究的目的:
- 探索新型合成路径,以在CRBN弹头中形成碳-碳键.
- 开发改进的CRBN结合剂,具有增强的药理特性.
主要方法:
- 使用高通量实验来选新的反应条件.
- 进行了基连接的CRBN结合剂的合成和表征.
- 对基连接与胺连接的CRBN结合剂进行了比较分析.
主要成果:
- 在CRBN弹头上创建碳-碳键的有效条件的发现.
- 与基连接的CRBN结合剂相比,与胺对应物相比,它们表现出更高的细胞透性.
- 与基连接的结合剂显示出降低了新基质活性和改进的选择性概况.
结论:
- 在PROTAC设计中,基连接点代表了CRBN结合剂的有价值修改.
- 开发的协议可以合成具有增强性质的PROTACs,例如提高BRD4降解选择性.
- 这项工作扩大了PROTAC开发的化学空间,为针对具有挑战性的疾病蛋白提供了新的途径.
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