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在Cereblon传感器循环中使用硫 - 异环交换的共价拼接使用histidine

Justin T Cruite^1,2, Radosław P Nowak^1,2, Katherine A Donovan^2,3

¹Center for Protein Degradation, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States.

ACS medicinal chemistry letters

|November 17, 2023

概括

新的共价药物策略针对氨酸以外的特定氨基酸,增强药物开发. 修改后的硫伊米达化合物表现出更好的稳定性,并有效地向蛋白质中的胺残留物.

科学领域:

药用化学医学化学
化学生物学化学生物学
药物发现药物发现药物发现

背景情况:

局部特异性蛋白质修饰扩大了可药物的蛋白质组,超出了氨酸残留物.
协价调节器提供了增强的目标参与和延长的作用时间.
之前使用硫尼尔化物和三醇电友的脑 (CRBN) 向共价探针 (EM12) 显示出较差的血稳定性.

研究的目的:

为药物开发开发开发新的共价调制剂,以提高代谢稳定性.
通过使用硫烯交换化学,探索定胺残留物的向.
为了提高cereblon (CRBN) 的稳定性,针对的共价探头.

主要方法:

在分子降解剂支架中加入硫尼尔皮拉,伊米达和核基.
评估人体血,肝脏显微体和肝细胞中的代谢稳定性.
在CRBN传感器循环中评估His353的共价标记效率.

主要成果:

通过新型弹头减弱内在反应性,显著提高了等离子体稳定性.
硫胺醇 (EM12-SO2Im) 显示出良好的代谢稳定性,并有效地阻断了CRBN结合部位.
几个修改后的化合物保留了His353的高效标签,表明成功的特定地点准.

结论:

硫-醇交换 (SuDEx) 弹头,特别是硫胺醇,适合于共价药物开发.
特定于位点的西斯蒂丁向是一种有前途的治疗策略.
增强的代谢稳定性为开发强大的共价疗法开辟了道路.

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