鉴定[3,2-d]胺衍生物作为强效和选择性的Janus激酶1抑制剂
Younghoon Kim1, Eunhye Jeon2, Hyunwoo Ahn3
1KU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul, 02841, Republic of Korea; Department of Biomedical Sciences, Graduate School of Medical Science, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.
European journal of medicinal chemistry
|February 1, 2025
概括
新的基[3,2-d]胺衍生物显示出强有力的和选择性的抑制Janus激酶1 (JAK1). 这些化合物通过诱导NSCLC细胞的亡和细胞循环停止来表现出显著的抗癌活性.
科学领域:
- 药用化学 医学化学
- 在瘤学瘤学.
- 分子生物学分子生物学
背景情况:
- 简氏激酶1 (JAK1) 是JAK-STAT信号通路的致癌激活的一个关键驱动因素.
- JAK1是抗癌药物发现的有希望的目标.
研究的目的:
- 设计和合成新型thieno[3,2-d]pyrimidine衍生物作为强效和选择性的JAK1抑制剂.
- 在非小细胞肺癌 (NSCLC) 模型中评估这些衍生物的抗癌疗效.
主要方法:
- 在设计和合成[3,2-d]胺衍生物时,采用了脚手架形态化策略.
- 对370种酶进行了全基因组选择性分析.
- 进行了结构-活动关系 (SAR) 研究.
- 使用了体外酶分析和基于细胞的分析 (抗增殖,细胞亡,细胞循环停止,殖民地形成).
主要成果:
- 化合物24被确定为一种强效和高度选择性的JAK1抑制剂.
- 与AZD4205 (9) 相比,衍生品25和46对JAK1比JAK2和JAK3具有更好的选择性.
- 化合物46对抗JAK1的酶活性是化合物9的4倍 (IC50=0.022μM),而不是9.
- 化合物25和46与化合物9相比,在NSCLC细胞上的抗增殖活性增强了5倍以上.
- 与9.化合物相比,24,25和46的衍生物诱导了更强的亡,细胞循环停止和减少NSCLC细胞中的殖民地形成.
结论:
- 设计的[3,2-d]胺衍生物代表了一类有前途的选择性JAK1抑制剂.
- 这些化合物通过抑制JAK1信号传递,具有显著的抗癌潜力.
- 这些发现为开发由JAK1激活驱动的癌症的新型向治疗提供了宝贵的见解.
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