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基于TF-PROTAC的 (GGAA) 能够有针对性的降解ETV6以抑制尤英肉瘤的生长

Zhichuan Zhu^1,2, He Chen³, Xing Qiu³

¹Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.

Journal of the American Chemical Society

|April 11, 2025

概括

研究人员开发了新的d ((GGAA) 3s,可以降低ETV6,这是Ewing肉瘤的脆弱性. 这种基于核酸的疗法抑制了癌症的生长,并显示了组合治疗的潜力.

科学领域:

癌症学
分子生物学
药物发现

背景情况:

尤文瘤是一种由EWS::FLI1驱动的儿科癌症,是一种具有挑战性的药物标.
ETV6是Ewing肉瘤中新发现的漏洞,与EWS::FLI1竞争.
目前没有针对ETV6的治疗方法.

研究的目的:

发现和开发一种针对尤文肉瘤的新疗法.
制造能够专门降解ETV6的基于核酸的药物.

主要方法:

设计和合成一种针对ETV6的独特 (GGAA) 3DNA寡核酸.
通过将 (GGAA) 3与VHL配体结合,开发基于 (GGAA) 3的TF-PROTACs (d(GGAA) 3s).
对d(GGAA) 3s在降解ETV6和抑制尤宁肉瘤细胞生长中的有效性进行评估.

主要成果:

(GGAA) 3寡核酸特别结合ETV6,而不是EWS::FLI1.
在Ewing肉瘤细胞中有效降解内源性ETV6,抑制瘤生长.
增强了EWS:FLI1活动,诱导细胞应激,并使细胞对化疗敏感.
在乳腺癌中,GGAA3还向ETV6融合蛋白.

结论:

d(GGAA) 3s 是一种基于核酸的新方法来降解ETV6.
这种策略有效地抑制了尤文瘤的生长,并有可能治疗其他依赖ETV6的癌症.
对于尤文瘤和相关恶性瘤来说,GGAA3s是一个有前途的治疗途径.

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