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曼尼希基 PIP-199 是一种化学不稳定的全分析干扰化合物

Xinyi Wu¹, Haritha Krishna Sudhakar¹, Lisa J Alcock¹

¹School of Chemistry, The University of Sydney, Eastern Avenue, Camperdown, NSW 2006, Australia.

Journal of medicinal chemistry

|August 9, 2023

概括

据认为抑制FANCM-RMI的小分子PIP-199,在溶液中迅速分解. 它的分解产物,而不是PIP-199本身,可能导致观察到的细胞效应,质疑其作为研究工具的实用性.

科学领域:

生物化学生物化学
分子生物学分子生物学
遗传学是一个遗传学.

背景情况:

据报道,PIP-199是唯一针对Fanconi贫血补充组M-RecQ介导的基因组不稳定性蛋白 (FANCM-RMI) 相互作用的小分子抑制剂.
这种FANCM-RMI相互作用对于调节Fanconi贫血和Bloom综合征中的基因组不稳定性至关重要.
包括PIP-199在内的Indole衍生的Mannich基类相应物已被用于各种生物研究中的研究工具.

研究的目的:

报告PIP-199及其类型的合成.
评估PIP-199和相关化合物的稳定性和抑制活性,以对抗FANCM-RMI.
确定PIP-199作为生物研究中的工具化合物的可靠性.

主要方法:

化学合成PIP-199和类似物.
在水性缓冲器和有机溶剂中评估化合物的稳定性.
生物物理测定 (约束性和竞争性) 来测试FANCM-RMI抑制.

主要成果:

PIP-199在常见的水性缓冲器和一些有机溶剂中立即分解.
无论是PIP-199还是其更稳定的类似物,都没有在FANCM-RMI结合试验中表现出可测量的活性.
显而易见的PIP-199细胞活性归因于其分解产品的非特异性毒性.

结论:

由于其不稳定性和缺乏特定的FANCM-RMI抑制活性,PIP-199不是一种有效的工具化合物.
观察到的PIP-199细胞效应很可能是由于其分解产品的非特异性毒性.
具有这种支架的曼尼克基化合物可能构成一种新的泛试验干扰化合物 (PAINS) 类,需要严格的稳定性评估.

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