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使用E3结合酶GID4用于向蛋白质降解的PROTACs的设计

Yanran Li¹, Kaiwen Bao¹, Jiyue Sun¹

¹Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education), Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, State Key Laboratory of Experimental Hematology, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China.

Nature structural & molecular biology

|April 28, 2025

概括

研究人员开发了使用GID4 E3结合酶降解BRD4.4的新型蛋白质溶解向嵌合体 (PROTACs). 这种新的PROTAC方法显示了抗癌疗法的潜力,因为它使向蛋白质降解成为可能.

科学领域:

生物化学和分子生物学
化学生物学化学生物学
药物发现和开发药物发现和开发

背景情况:

化向化体 (PROTACs) 使用无素-蛋白酶体系统进行选择性蛋白质降解.
现有的PROTACs仅限于人类E3酶的一小部分,阻碍了更广泛的应用.
针对难以处理的基质仍然是药物发现的挑战.

研究的目的:

探索E3结合酶GID4 (葡萄糖诱导的降解缺陷复合体4) 作为PROTAC介导的蛋白质降解的新目标.
设计和验证基于GID4的PROTAC用于新基质的降解,例如BRD4.
阐明GID4-PROTAC-BRD4复合物的形成和降解背后的结构和分子机制.

主要方法:

设计和合成GID4招募的PROTAC分子.
以GID4和ubiquitin-proteasome系统依赖的方式评估BRD4降解.
在体外和体内评估PROTAC的抗增殖和抗瘤活性.
确定GID4-PROTAC-BRD4三元复合物的晶体结构.

主要成果:

成功开发基于GID4的PROTACs,如NEP162,能够消除内源的BRD4.
在异种移植模型中,NEP162表现出显著的抗增殖活性和抑制瘤生长.
晶体结构揭示了GID4和BRD4之间明显的三元复杂状态和塑性相互作用,解释了对降解的招募.

结论:

使用小分子PROTACs,可以有效地利用E3结合酶GID4进行向蛋白质降解.
基于GID4的PROTAC,如NEP162,通过向BRD4.4来为抗癌药物发现提供了一个有希望的新途径.
结构洞察力为GID4介导的向降解提供了分子基础,扩大了用于PROTAC应用的E3链酶谱.

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