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发现一种基于胺酸的HDAC11同型选择性抑制剂,具有口服抗AML功效

Qipeng Chai¹, Maoshuo Yang², Chunxi Liu³

¹Department of Medicinal Chemistry, State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Key Laboratory of Chemical Biology (Ministry of Education), Shandong Key Laboratory of Druggability Optimization and Evaluation for Lead Compounds, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Ji'nan 250012, P. R. China.

Journal of medicinal chemistry

|March 6, 2026

概括

研究人员优化了A9化合物,制造了25化合物,这是一种强大的HDAC11抑制剂,用于治疗急性髓性白血病 (AML). 化合物25在小鼠中显示出优异的抗AML作用和口服疗效,单独或与ivosidenib一起使用.

科学领域:

药用化学医学化学
药理学药理学是指药理学的学科.
血液学血液学血液学

背景情况:

海斯脱乙酶11 (HDAC11) 是急性髓性白血病 (AML) 的验证治疗标.
化合物A9,一种特定的HDAC11抑制剂,在之前的研究中被确定.

研究的目的:

开发具有增强药物样性质的新型,特定的HDAC11抑制剂.
优化化合物A9的结构,以改善抗AML活性.

主要方法:

结构-活性关系 (SAR) 研究和A9衍生物的合成.
在体外测试评估HDAC11抑制,抗AML作用和药物动力学特性.
在体内研究使用MLL-AF9诱导的AML的小鼠模型.

主要成果:

与A9.9相比,化合物25成为一种强效和选择性的HDAC11抑制剂,与A9.9相比,改善了肝脏微小体稳定性.
化合物25比FT895具有优越的抗AML疗效,包括增殖抑制,亡诱导,细胞循环停止,分化促进和铁亡诱导.
化合物25与ivosidenib结合时表现出协同作用的抗AML作用,并在小鼠AML模型中显示出良好的口服药理动力学和疗效.

结论:

化合物25为AML治疗提供了一个有前途的下一代HDAC11抑制剂.
化合物25和ivosidenib的组合为AML提供了一个强大的协同治疗策略.
化合物25的良好的口服生物可用性支持其在AML治疗中临床开发的潜力.

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