基于碎片的发现使得黑色素瘤瘤基因MITF的直接向成为可能
Deborah Castelletti1, Jürgen Hinrichs2, Goran Malojčić3
1Novartis Biomedical Research, Basel, Switzerland. deborah.castelletti@novartis.com.
Nature communications
|December 9, 2025
概括
研究人员发现了新的方法来准黑色素瘤中的微相关转录因子 (MITF). 这一发现为开发高级转移性黑色素瘤患者的持久治疗提供了有希望的新途径.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 药物发现 药物发现 药物发现
背景情况:
- 晚期转移性黑色素瘤缺乏持久的治疗选择.
- 微相关转录因子 (MITF) 在黑色素瘤进展中起着至关重要的作用.
- 针对像MITF这样的转录因子是一个重大的治疗挑战.
研究的目的:
- 发现可以直接准MITF的DNA结合域的连接体.
- 建立在黑色素瘤治疗中药理抑制MITF的基础.
主要方法:
- 基于碎片的选 (FBS) 使用核磁共振 (NMR) 识别初始的MITF结合碎片.
- 基于结构的设计,X射线晶体学和生物物理技术以优化碎片亲和力.
- 核磁共振实验和分子动力学模拟以阐明联体诱导的构造变化.
主要成果:
- 识别了MITF扭曲口袋的初始弱结合碎片.
- 优化碎片通过基于结构的设计来实现亚微分子亲和度.
- 揭示了MITF同位体中的动态形状交换的联体诱导扰乱.
结论:
- 证明了直接准基本螺旋环螺旋氨酸拉链 (bHLH-LZ) 转录因子的DNA结合域的可行性.
- 建立了开发针对黑色素瘤中MITF的新疗法策略的基础.
- 提升了对涉及动态蛋白质构造的蛋白质-连接体相互作用的理解.
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