含有碳胺的泛比诺斯塔特类似物,旨在与E103-D104在I类HDAC异型体腔开口处相互作用,并与E103-D104相互作用
Callum A Rosser1, Samuel V Feeney1, Lukas Roth1
1School of Medical Sciences, The University of Sydney, Sydney, New South Wales 2006, Australia.
ACS medicinal chemistry letters
|February 19, 2025
概括
与胺基组组合的泛比诺斯塔特类似物被合成,以向与癌症相关的素脱乙酶 (HDACs). 这些类似物与原始化合物Panobinostat相比,对HDAC2的效果有所降低.
科学领域:
- 药用化学 医学化学
- 生物化学 生物化学
- 癌症生物学 癌症生物学
背景情况:
- 帕诺比诺斯塔特抑制了依赖的基因素脱乙酶 (HDACs),这是癌症治疗中的关键标.
- 第I类HDAC与各种癌症有关,这使得它们成为药物开发的有吸引力的目标.
研究的目的:
- 为了合成和评估新型的Panobinostat类似物,其中包括碳胺组.
- 调查这些类似物在HDAC2抑制方面的结构-活性关系.
- 探索通过形成键与HDAC活性部位中的酸性残留物增强结合的潜力.
主要方法:
- 合成了三组具有碳胺功能的帕诺比诺斯塔特类型药物.
- 在体外评估合成的类似物作为HDAC2的抑制剂,确定IC50值.
- 组合对接研究,以预测HDAC2活性部位内的结合模式和相互作用.
主要成果:
- 所有合成的帕诺比诺斯塔特类似物与帕诺比诺斯塔特 (IC50 = 5 nM) 相比,对HDAC2的功效较低 (IC50范围:150-3320 nM).
- 最强效的类似物,S-3 (IC50 = 150 nM) 和S-2 (IC50 = 350 nM),通过它们的碳胺NH2组与E103和D104形成键.
- 在类似物中观察到减少的pKa值,这是由于吸收电子的碳胺组.
- 对接研究表明,减少静电结合,溶解和硬质因素抵消了增加结合的好处.
结论:
- 将碳胺基组引入帕诺比诺斯塔特类似物并没有增强HDAC2抑制功效.
- 观察到与酸性残留物 (E103,D104) 形成键,但不足以克服降低的结合亲和力.
- 合成的类似物不太可能对I类HDAC具有显著的异型选择性.
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