发现强效和选择性可逆的乌比奎丁类修饰剂激活酶5抑制剂,向UFMylation途径
James J Mignone1, Elizabeth A Jurica1, Deepa Rajasekaran1
1Bristol Myers Squibb Research & Early Development, Princeton, New Jersey 08543, United States.
Journal of medicinal chemistry
|September 25, 2025
概括
研究人员开发了强大的UBA5抑制剂,49和50,准了在癌症等疾病中至关重要的UFMylation途径. 这些选择性化合物为研究UFMylation和相关的细胞功能提供了有价值的工具.
科学领域:
- 生物化学 生化学
- 分子生物学分子生物学
- 药物发现 药物发现 药物发现
背景情况:
- 乌比奎丁类修饰剂激活酶5 (UBA5) 是UFMylation通路中的E1酶.
- UFMylation在细胞功能中起着至关重要的作用,是包括癌症在内的疾病的潜在治疗点.
研究的目的:
- 发现和合成UBA5.5的强效和选择性非对应性抑制剂.
- 为研究UFMylation路径提供有价值的工具化合物.
主要方法:
- 高通量屏幕的结构-活动关系优化 (组合 6).
- 利用了传统和微量图书馆合成.
- 采用表面等离子体共振,纳米差异扫描度和细胞热转移试验用于生物物理和细胞目标参与验证.
主要成果:
- 已确定49和50的化合物是强效和选择性的非对应性UBA5抑制剂.
- 在视网膜色素上皮层-1细胞中证明抑制了UBA5,UFC1和RPL26的UFMylation.
- 对UBA5而言,化合物49和50的确定的特异性超过其他E1-E2转化途径.
结论:
- 发现和合成强效和选择性UBA5抑制剂 (化合物49和50).
- 这些抑制剂显示出作为研究UFMylation通路的工具化合物的前景.
- 这些发现支持UBA5作为UFMylation相关疾病中可行的治疗点.
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