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在小鼠模型中,小分子抑制YTHDC1作为对抗急性髓性白血病的策略

Hailin Zhang^1,2, Yueshan Li^1,2, Yin Zhao³

¹Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.

Science translational medicine

|February 4, 2026

概括

一种名为YL-5092的新药有效地准了YTHDC1,这是一种参与癌症的RNA阅读器. 这种选择性抑制剂通过诱导癌细胞死亡和分化,在治疗急性髓性白血病方面表现有前途.

科学领域:

分子生物学分子生物学
在瘤学瘤学.
药物发现药物发现药物发现

背景情况:

RNA N6 - - 甲基氨酸 (m6A) 读者的失调与各种疾病有关.
针对小分子的m⁶A读者提供治疗潜力.

研究的目的:

识别和描述一种新,强效和选择性的核能抑制剂 A 阅读器 YTHDC1.1.
在急性髓性白血病 (AML) 模型中评估YTHDC1抑制剂YL-5092的治疗疗效.

主要方法:

与抑制剂YL-5092一起对YTHDC1进行联合结晶,以确定高分辨率结构.
使用AML模型进行体外和体内研究,以评估YL-5092对YTHDC1结合,mRNA稳定性,亡和分化的影响.
在异种移植模型中对YL-5092的评估,包括组合治疗和白血病干细胞活性评估.

主要成果:

YL-5092选择性地抑制YTHDC1,阻止其与m6A基质的相互作用,并降低mRNA的稳定性.
用YL-5092治疗诱导AML细胞的亡和骨髓分化.
YL-5092在多种AML异种移植模型中表现出有效性,无论是单剂还是组合疗法,导致白血病消除和延长存活时间.
抑制剂选择性地损害了白血病干细胞,同时保留了正常的造血细胞.

结论:

YL-5092是一种强效和选择性的YTHDC1第一类抑制剂,在AML中具有显著的治疗潜力.
针对像YTHDC1这样的m⁶A读者是治疗血液恶性瘤的一个有希望的策略.

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