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为第一批GPX4和CDK双抑制剂进行设计,合成和生物评估

Jiangmin Zhu¹, Yuxing Cai¹, Min Kong¹

¹Jiangsu Key Laboratory of Bioactive Natural Product Research, State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China.

Journal of medicinal chemistry

|January 31, 2024

概括

研究人员开发了一种针对铁和细胞循环进展的双重抑制剂,用于癌症治疗. 化合物B9有效抑制谷氨过氧化酶4 (GPX4) 和循环素依赖性激酶 (CDK),在体外和体内表现出强大的抗癌活性.

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:

结合铁和其他细胞死亡途径,为癌症治疗提供了治疗优势.
在GPX4抑制剂 (ML162) 和CDK抑制剂 (indirubin-3'-oxime) 之间观察到协同作用的抗癌作用.

研究的目的:

设计和合成针对GPX4和CDKs的新型双重抑制剂.
评估这些双重抑制剂的抗癌潜力.

主要方法:

一系列GPX4和CDK双抑制剂的合成.
在体外细胞毒性测定对多个癌症细胞系.
对GPX4和CDK 4/6.6进行酶抑制试验.
细胞周期分析和铁灭诱导研究.
在小鼠模型中的体内疗效研究.

主要成果:

化合物B9在四个细胞系中表现出显著的细胞毒性活性.
B9 强烈抑制了GPX4 (IC50 = 542.5 nM) 和选择性地抑制了CDK 4/6 (IC50 = 191.2/68.1 nM).
在MDA-MB-231和HCT-116细胞中,B9诱导了铁亡和G1阶段停止.
与单位抑制剂相比,B9在体内表现出优异的癌症生长抑制.

结论:

双抑制GPX4和CDKs是癌症治疗的一个有希望的策略.
化合物B9是一种强大的双重抑制剂,具有显著的治疗潜力.
进一步开发GPX4/CDK双抑制剂可能会导致有效的恶性癌症治疗.

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