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具有细胞膜透性的循环的分子设计和MDMX-p53抑制剂的开发

Mai Mizuno-Kaneko¹, Ichihiko Hashimoto², Kenta Miyahara²

¹Synthetic Organic Chemistry Laboratories, FUJIFILM Corporation, 577, Ushijima, Kaisei-machi, Ashigarakami-gun, Kanagawa 258-8577, Japan.

ACS medicinal chemistry letters

|September 22, 2023

概括

循环可以抑制蛋白质-蛋白质相互作用 (PPI),但与细胞进入作斗争. 这项研究通过分析膜中的体构成,确定了一种具有改善细胞膜透性的循环,从而产生了强大的MDMX抑制剂.

科学领域:

药用化学医学化学
分子生物学分子生物学
生物物理学的生物物理.

背景情况:

循环对于抑制细胞内蛋白与蛋白相互作用 (PPI) 是有前途的.
然而,由于细胞膜的透性差,它们的治疗应用受到限制.
了解膜通道的形状要求至关重要.

研究的目的:

通过被动扩散来研究循环质细胞膜透性的构造基础.
通过利用这些透性要求,识别MDMX的高亲和度循环抑制剂.
开发针对细胞内PPI的新型治疗剂.

主要方法:

计算化学被用来选具有对MDMX.高亲和力的循环结构.
在细胞膜环境中分析周期性形状.
细胞膜透性 (Papp) 和抑制活性 (IC50) 的评估.

主要成果:

确定了一种特定的循环,被指定为循环19 .
循环19显示出显著的细胞膜透性 (Papp = 0.80 × 10^-6 cm s^-1).
该化合物对MDMX具有强烈的抑制活性,IC50为0.07μM.

结论:

这项研究阐明了在循环中增强细胞膜透性的构造要求.
循环19代表了细胞内PPI抑制的有希望的化合物,特别针对MDMX.
这项工作为设计用于治疗应用的细胞透性循环提供了一种策略.

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