在选择性HDAC8抑制剂PCI-34051中替换酸组
Keith Long1, David A Close1, Paul A Johnston1
1Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, United States.
Bioorganic & medicinal chemistry letters
|May 23, 2024
概括
研究人员探索了用其他结合部分替换HDAC8抑制剂PCI-34051中的酸 (HA) 组. 修改后的化合物失去了效力,这表明生物异构体替代结合基因的挑战.
科学领域:
- 药用化学 医学化学
- 酶抑制可以抑制酶.
- 药物发现 药物发现 药物发现
背景情况:
- PCI-34051是一种HDAC8的选择性抑制剂,是潜在治疗的目标.
- 它进入临床试验受到阻碍,可能是由于药理动力学问题或非目标效应.
- 在PCI-34051中的酸 (HA) 组可能有助于这些限制.
研究的目的:
- 研究酸 (HA) 组在PCI-34051的活性和潜在限制中的作用.
- 探索替代结合部分作为HA组的替代品.
- 评估这些替代品对HDAC8抑制和亲和力的影响.
主要方法:
- 合成PCI-34051类似物与修改的结合组.
- 在HDAC8酶分析中评估化合物活性.
- 对合成类型的结合亲和力的评估.
主要成果:
- 对于HA组而言,没有一个经过测试的生物异构体替代品能够有效地模仿其功能.
- 与PCI-34051.1.相比,合成的类似物表现出明显降低的功效.
- 同类药物在与HA组相同的范围内对的亲和力是可以忽略不计的.
结论:
- 酸 (HA) 组对于PCI-34051对HDAC8.8的功效至关重要.
- 对HA组的直接生物异构替代对维持结合亲和力和抑制活性具有挑战性.
- 这些发现凸显了设计HDAC8抑制剂的困难,即通过替代正规的结合模式来设计.
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