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Updated: Jun 24, 2025

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一种新的FAK降解PROTAC分子表现出抗瘤活性和有效的MDR逆转效应

Ming-Shi Xu¹, Xiao-Fan Gu¹, Cong Li¹

¹Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200062, China.

Acta pharmacologica Sinica

|June 6, 2024

概括

一种新的PROTAC分子F2有效地抑制癌细胞生长,并通过向FAK (焦点粘附激酶) 来逆转多药性耐药性. 这种针对FAK的PROTAC分子在癌症治疗中有望克服抗药性.

科学领域:

在瘤学瘤学.
分子生物学分子生物学
药物发现药物发现药物发现

背景情况:

焦点粘附激酶 (FAK) 在癌症的进展和药物耐药性的发展中起着至关重要的作用.
现有的FAK抑制剂主要向激酶活性,忽视了FAK作为支架蛋白质的重要性.
向FAK为癌症提供了潜在的治疗策略,单独或结合治疗.

研究的目的:

设计和评估一种针对FAK的新型PROTAC分子 (蛋白质溶解向的奇默分子).
评估针对FAK的PROTAC在抑制癌细胞增殖和逆转多药耐药性 (MDR) 的有效性.
研究PROTAC抗瘤和MDR逆转作用的潜在机制.

主要方法:

基于使用PROTAC技术的FAK抑制剂IN10018的新型FAK向PROTAC分子F2的设计.
评估F2对各种癌细胞系 (4T1,MDA-MB-231,MDA-MB-468,MDA-MB-435) 的抑制活性.
评估F2在耐药细胞系 (HCT8/T,A549/T,MCF-7/ADR) 中逆转多药耐药性的能力,并调查其对信号通路 (AKT,ERK) 和EMT的影响.

主要成果:

在多个细胞系中,F2表现出强大的癌细胞生长抑制,IC50值较低.
F2显著逆转了耐药癌细胞中的多药性耐药性,其效果优于母抑制剂IN10018.
对于MDR来说,最高的逆转折幅达到了158倍,表明了实质性的疗效.
F2的抗瘤和MDR逆转作用可能通过抑制AKT和ERK信号通路和调节上皮质-介质细胞过渡 (EMT) 来调节.
发现F2降低了HCT8/T细胞中的P-gp蛋白水平,有助于药物耐药性的逆转.

结论:

据报道,F2是首个针对FAK的PROTAC分子,在逆转化疗药物耐药性方面已证明有效.
新的PROTAC分子F2为克服癌症生长和多药耐药性提供了一个有前途的治疗策略.
这些发现支持进一步研究针对FAK向的PROTACs,用于强大的体内抗癌应用.

关键词:

FAK 抑制剂的使用在MDR的反转过程中,MDR的反转在P-gpp中使用P-gp.这就是PROTAC.它具有抗瘤活性.

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