选择性BRD7odomain抑制剂的合理设计和开发以及它们在前列腺癌中的活性
Sandra C Ordonez-Rubiano1, Chad A Maschinot1, Sijie Wang1
1Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University. Robert Heine Pharmacy Building 575 Stadium Mall Drive, West Lafayette, Indiana 47907, United States.
Journal of medicinal chemistry
|August 8, 2023
概括
研究人员开发了一种选择性化学探针,用于检测含odomain蛋白7 (BRD7),这是一种涉及癌症的蛋白质. 这些新型抑制剂针对独特的结合口袋,为研究BRD7提供了新的工具.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 化学生物学 化学生物学
背景情况:
- 含有基多马因的蛋白质是乙化素的表观遗传阅读器.
- 含原体的蛋白7 (BRD7) 涉及到各种癌症.
- 目前缺乏针对BRD7的选择性化学探测器.
研究的目的:
- 识别和开发用于含odomain蛋白7 (BRD7) 的选择性化学探针.
- 通过化学生物学方法研究BRD7在癌症中的功能.
主要方法:
- 使用了BRD7和BRD9体 (BDs) 的结晶结构.
- 设计和合成的配体准BRD7独家结合口袋.
- 进行了结合亲和度测定和结合模式分析.
- 在基于细胞的前列腺癌模型中验证了化合物选择性和效用.
主要成果:
- 确定了一个独特的绑定口袋,仅限于BRD7.
- 开发了两种选择性BRD7抑制剂,1-78和2-77,具有亚微分子亲和力.
- 证明了抑制剂占据了一个独特的裂并保持关键相互作用.
- 在前列腺癌细胞模型中验证了化合物选择性和有效性.
结论:
- 开发了第一个针对BRD7.7的选择性化学探针.
- 这些探针为研究BRD7在癌症中的作用提供了宝贵的工具.
- 这些发现为进一步研究BRD7向治疗铺平了道路.
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