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选择性USP7抑制剂的结构导向发现具有体外活性

Attila Vasas¹, Lisa Ivanschitz², Balázs Molnár¹

¹Servier Research Institute of Medicinal Chemistry, Záhony u. 7., Budapest H-1031, Hungary.

Journal of medicinal chemistry

|October 23, 2024

概括

研究人员优化了一种向无素特定蛋白酶7 (USP7) 的化合物,该蛋白质是癌症中的关键蛋白质. 改进的化合物实现了高亲和力,证明了瘤的向参与,并在临床前癌症模型中显示出有效性.

科学领域:

生物化学生物化学
药用化学医学化学
在瘤学瘤学.

背景情况:

乌比奎丁特异性蛋白酶7 (USP7) 是瘤学中已验证的标.
基于结构的药物设计对于优化小分子抑制剂至关重要.

研究的目的:

优化低微分子USP7抑制剂,以达到高亲和度和体内疗效.
探索结构-活动关系围绕一个定义不佳的USP7.7的绑定口袋.

主要方法:

结构导向药物设计使用USP7抑制剂的晶体结构.
复合库的高通量选,以识别最初的命中.
系统的化学修饰和选替代剂以提高亲和力.
在体内研究,包括异种移植模型中的目标参与,耐受性和疗效.

主要成果:

抑制剂的一个区域的优化导致了结合亲和力的显著增加.
优化的化合物实现了对USP7.7的低纳米系亲和力.
化合物在瘤中表现出向参与,并且在小鼠中耐受良好.
在临床前的异种移植癌症模型中观察到显著的疗效.

结论:

结构引导优化USP7抑制剂可以产生强效的药物候选者.
针对USP7代表了对各种癌症的有希望的治疗策略.
开发的化合物显示出在瘤学领域进一步临床开发的潜力.

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