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针对T315I突变的新型BCR-ABL氨酸激酶抑制剂的结构优化,合成和生物活性评估

Shuo Wang¹, Jingjing Chen¹, Rui Hou¹

¹School of Pharmacy, Lanzhou University, 199 West Donggang Rd., 730000, Lanzhou, China.

Chemico-biological interactions

|September 27, 2024

概括

开发了针对慢性髓性白血病 (CML) 中BCR-ABL T315I突变的新型氨酸激酶抑制剂. 两种化合物,W4和W8,显示出有希望的选择性和细胞死亡诱导作用对抗性CML细胞.

科学领域:

在瘤学瘤学.
药用化学医学化学
分子生物学分子生物学

背景情况:

慢性骨髓性白血病 (CML) 是由BCR-ABL融合蛋白驱动的,由铁氨酸激酶抑制剂 (TKIs) 作为点.
药物耐药性,特别是T315I突变,以及像Ponatinib这样的现有TKIs的心脏毒性,带来了重大的临床挑战.
技术知识产权的结构优化是克服阻力和改善安全配置文件的关键策略.

研究的目的:

通过虚拟选和结构优化,识别新的BCR-ABL/T315I氨酸激酶抑制剂.
评估新开发的化合物对T315I突变的CML的疗效和选择性.

主要方法:

虚拟选使用ZINC21710815作为化合物对抗BCR-ABL/T315I.
化合物的结构优化.
新型化合物W4和W8在BaF3/T315I细胞中的活性评估和机制研究.

主要成果:

确定了一系列新的BCR-ABL/T315I氨酸激酶抑制剂.
化合物W4和W8表现出增强的细胞死亡诱导作用.
W4和W8对BaF3/T315I细胞具有显著的选择性.

结论:

新型化合物W4和W8显示出作为化合物开发更有效的抗CML药物的潜力.
这些化合物需要进一步研究它们在克服T315I介导耐药性的治疗潜力.

关键词:

在 BCR-ABLL 中.在CML中,CML是CML.结构优化结构优化在T315I中使用.

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