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发现基于化的PI3K/HDAC双抑制剂,在淋巴瘤细胞中增强了亲亡活性

Baogeng Hou¹, Geng Jia¹, Zhongqiang Li¹

¹Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China.

European journal of medicinal chemistry

|April 29, 2025

概括

结合PI3K和HDAC通路的新型双抑制剂在癌症治疗中显示出有前途. 这些新化合物有效地抑制瘤细胞的生长并诱导细胞亡,提供了潜在的新疗法策略.

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:

氨基酸3-酶 (PI3K) 和基因素脱乙酸酶 (HDAC) 在各种癌症中经常过度表达.
同时抑制PI3K和HDAC通路可能通过抑制瘤增殖和诱导亡,提供协同作用的抗癌效应.

研究的目的:

合理设计和合成PI3K和HDAC的新型双抑制剂.
评估合成化合物的抑制活性和抗增殖作用.

主要方法:

通过将PI3K抑制剂ZSTK474药与HDAC抑制剂11h部分集成,设计和合成新型化合物.
在体外评估PI3K异型 (α,β,γ,δ) 和HDAC1-3.3的抑制活性.
对各种瘤细胞系的抗增殖活性和在地幔细胞淋巴瘤Jeko-1细胞中诱导亡的评估.

主要成果:

代表性化合物31f表现出强大的PI3K (IC50 = 2.580.5 nM) 和HDAC1-3 (IC50 = 1.975.5 nM) 抑制活性.
化合物31f在多个瘤细胞系中表现出显著的抗增殖作用.
在Jeko-1细胞中,31f在诱导亡方面表现出优异的疗效,与单位抑制剂相比.

结论:

该研究成功开发了基于化的新型双PI3K/HDAC抑制剂.
化合物31f代表了在癌症治疗中进一步调查的有希望的领先候选人.
这些发现为下一代双抗癌剂的开发提供了宝贵的见解.

关键词:

这是一种抗瘤药物.这是一种HDAC/PI3K双位抑制剂.希斯脱乙酶的使用情况酸氨基醇-3-酶亲进细胞灭绝 (pro-apoptosis) 是一种前进细胞灭绝.

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