从HPOB衍生出的优先HDAC6抑制剂在与德丁联合使用时表现出协同作用的抗白血病活性
Maik Tretbar1, Julian Schliehe-Diecks2, Lukas von Bredow1
1Institute for Drug Discovery, Medical Faculty, Leipzig University, Brüderstraße 34, 04103, Leipzig, Germany.
European journal of medicinal chemistry
|May 7, 2024
概括
研究人员开发了新的基因素脱乙酶6 (HDAC6) 抑制剂. 这些化合物在与decitabine配对时,在治疗急性髓性白血病 (AML) 的联合治疗中表现有前途.
科学领域:
- 药用化学 医学化学
- 在瘤学瘤学.
- 生物化学 生物化学
背景情况:
- 基因组脱乙酶6 (HDAC6) 是对瘤和非瘤疾病的验证标.
- 选择性HDAC6抑制剂通常需要组合治疗以获得有效的抗癌活性.
研究的目的:
- 使用高效的Ugi反应合成新型HDAC6抑制剂类似物.
- 评估这些同类药物与decitabine结合的抗白血病活性和协同潜力.
主要方法:
- 通过两步Ugi四组分反应合成HPOB类似物.
- 生物化学测定用于HDAC抑制和细胞活力测定.
- 在急性髓性白血病模型中,与德西他的联合查.
主要成果:
- 确定了具有强烈抗白血病活性的化合物1g和具有强烈HDAC6抑制的化合物2b.
- 1g和2b两种药物在急性髓性白血病中都表现出与德西他的协同作用.
- 化合物2b表现出特别显著的协同作用与desiitabine.
结论:
- 新型HDAC6抑制剂通过Ugi反应有效合成.
- 结合HDAC6抑制剂和DNA甲基转移酶抑制剂,如德平,是AML治疗的一个有希望的策略.
- 这种方法可以改善急性髓性白血病的治疗结果.
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