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基于结构的发现强大的,口服生物可用的本佐克萨皮基WD重复域5抑制剂

Kevin B Teuscher, Jonathan J Mills, Jianhua Tian¹

¹Molecular Design and Synthesis Center, Vanderbilt Institute of Chemical Biology, Nashville, Tennessee 37232-0142, United States.

Journal of medicinal chemistry

|December 12, 2023

概括

研究人员优化了WDR5 WIN位点抑制剂,发现了一种新的佐西子支架. 这些新化合物显示出增强的功效和改善了抗癌药物开发的特性.

科学领域:

药用化学医学化学
癌症生物学癌症生物学
分子药理学分子药理学

背景情况:

WD重复域5 (WDR5) 是MYC的关键辅因子,并调节核糖体蛋白基因转录.
WDR5是固体和血液恶性瘤的验证的抗癌标.
之前的研究已经确定了基于二异诺林的WDR5 WIN位点抑制剂,具有临床前有效性.

研究的目的:

为了优化WDR5 WIN-site抑制剂的双循环核心.
发现具有增强功效和物理化学性质的新型WDR5抑制剂.
探索WDR5抑制的其他支架.

主要方法:

基于结构的药物设计利用X射线晶体学.
合成和优化基于佐胺的新型化合物.
在体外细胞测试以评估化合物的效能和选择性.

主要成果:

确定了3,4-二二[f][1,4]氧化-5(2H) - 一作为WDR5抑制剂的新型支架.
设计了部分和的双循环P7单元,以改善抑制性质.
与之前的化合物相比,基于佐西子的抑制剂显示细胞效能和选择性增加.
在新型抑制剂系列中获得了有利的物理化学性质.

结论:

佐西子支架代表了开发强大的WDR5 WIN-site抑制剂的有希望的替代方案.
优化的WDR5抑制剂表现出改善的细胞活性和类似药物的特性.
这些发现支持WDR5抑制剂作为新型抗癌疗法的发展.

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