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FANCM-RMI 相互作用的细胞活性抑制剂

Lisa J Alcock^1,2, Joshua Mills¹, Rohan Bythell-Douglas³

¹School of Chemistry, The University of Sydney, Camperdown, New South Wales 2006, Australia.

Journal of medicinal chemistry

|November 14, 2025

概括

研究人员开发了针对FANCM-RMI相互作用的新型抑制剂,这对于替代端粒延长 (ALT) 途径癌症至关重要. 这些细胞活性抑制剂显示出作为癌症研究工具的前景.

科学领域:

生物化学生物化学
分子生物学分子生物学
癌症研究癌症研究

背景情况:

FANCM-RMI蛋白相互作用对于替代延长端粒 (ALT) 途径至关重要,这是癌症用于实现复制性不朽的机制.
针对这种相互作用为ALT驱动的癌症提供了潜在的治疗策略.

研究的目的:

发现和描述FANCM-RMI蛋白质-蛋白质相互作用的第一个细胞活性抑制剂.
开发化学工具来研究FANCM-RMI在ALT阳性癌症中的作用.

主要方法:

选mRNA显示的类库使用1,4-二-2-丁.
使用纳米分子亲和度测量 (K_D) 对RMI的结亲和度的表征.
进行X射线晶体学以确定顶级抑制剂的结合模式.
在与细胞透结合后,对ALT阳性骨髓瘤细胞系的抗增殖作用的评估.

主要成果:

发现了强大的线性和循环抑制剂,可以在FANCM相互作用部位与纳米分子亲和力 (K_D = 4-31 nM) 结合RMI.
抑制剂超过了原生FANCM模仿剂 (IC₅₀ = 24-155 nM) 的竞争力.
X射线晶体结构揭示了顶部击和RMI之间的新奇相互作用.
穿透细胞的联体在ALT阳性骨髓瘤细胞中表现出抗增殖作用.

结论:

该研究报告了FANCM-RMI相互作用的第一个细胞活性抑制剂.
这些抑制剂是研究ALT驱动癌症中FANCM-RMI复合物的有价值的化学工具.
这些发现为针对使用ALT通路的癌症的治疗策略开辟了新的途径.

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