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基于结构的新型螺旋胺ASH1L抑制剂的开发

Guang Huang¹, Rhiannon Stevens¹, Devon G Hucek¹

¹Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, United States.

Journal of medicinal chemistry

|December 16, 2024

概括

研究人员开发出强大的ASH1L抑制剂,如AS-254s,以向致癌蛋白质. 这些新化合物在白血病细胞中显示出更好的活性和有效性,为新型癌症治疗提供了潜力.

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:

缺席的,小的,或同源类型的1 (ASH1L) 蛋白质是关键的氨酸甲基转移酶,涉及各种癌症,特别是白血病.
虽然ASH1L是一种有吸引力的治疗标,但迄今为止只发现了一类抑制剂.

研究的目的:

设计和开发针对其催化SET域的新型,强效和选择性ASH1L抑制剂.
与现有化合物相比,识别具有改善活性和细胞疗效的先进抑制剂.

主要方法:

使用基于结构的药物设计和广泛的药物化学努力.
使用生物化学试验评估了抑制活性 (IC50 = 94 nM对于66s/AS-254s).
细胞疗效在含有MLL1转位的白血病细胞中进行了评估,评估了增殖,亡和分化.

主要成果:

鉴定66s (AS-254s),一种具有显著增强活性的高度强效和选择性的ASH1L抑制剂.
AS-254s证明有效地阻断了白血病细胞增殖.
AS-254s成功诱导了MLL1转位的白血病细胞的亡和分化.

结论:

这项研究提供了一种高质量的化学探针,AS-254s,针对ASH1L催化SET域.
开发的抑制剂表现出增强的功效和细胞功效,对研究ASH1L功能有价值.
这些发现为开发针对ASH1L.的新型抗癌疗法铺平了道路.

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