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利用室内支架来识别调节XBP1mRNA拼接的小分子IRE1α抑制剂

Yang Liu^1,2,3, Amrutha K Avathan Veettil^1,2,3, Raphael Gasper⁴

¹Chemical Genomics Centre, Max Planck Institute of Molecular Physiology, Dortmund, Germany.

Nature communications

|September 26, 2025

概括

研究人员开发了新的基于醇的小分子,可以有效抑制需要内醇的酶1α (IRE1α). 这些强有力的IRE1α抑制剂向内分泌网膜压力,并显示出治疗相关人类疾病的前景.

科学领域:

生物化学生物化学
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:

需要内醇的酶1α (IRE1α) 是一种关键的传感蛋白,可以调节内细胞网膜 (ER) 的压力.
IRE1α控制X盒结合蛋白1 (XBP1) mRNA拼接和下游展开蛋白质反应 (UPR) 途径.
IRE1α的失调与各种人类疾病有关,突出显示了其治疗潜力.

研究的目的:

识别和描述针对IRE1α的新型小分子.
研究这些化合物的抑制机制和治疗潜力.

主要方法:

合成和选作为IRE1α抑制剂的替代性内醇.
共同晶体结构的确定以阐明抑制模式.
细胞测试以评估ER压力诱导的XBP1mRNA拼接的抑制.

主要成果:

确定了一系列强效和选择性取代的基于醇的IRE1α抑制剂,包括IA107.
共同晶体结构显示IA107通过结合激酶域而无影响二分化而全质抑制IRE1α RNase活性.
IA107证明了细胞XBP1mRNA拼接的度依赖抑制,前药物显示活性增强约50倍.

结论:

替代的内醇代表了开发强效和选择性的IRE1α抑制剂的有前途的化学型.
这些化合物调节RNA剪接,并为IRE1α向治疗提供了扩展的治疗应用.
这些发现支持开发用于治疗IRE1α失调疾病的小分子.

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