Zeng Huajie, Fang Zhiguo, Feng Yinghua, Su Tong, Miao Weibing, Wang Zihua
Fujian Provincial Key Laboratory of Brain Aging and Neurodegenerative Diseases, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian 350122, China.
CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, China.
Mol Pharm. 2025 Jun 2;22(6):3286-3296. doi: 10.1021/acs.molpharmaceut.5c00219. Epub 2025 May 14.
Proteolysis-targeting chimeras (PROTACs) represent a promising strategy for addressing ″undruggable″ proteins in cancer therapy. However, challenges such as poor bioavailability, limited cellular permeability, and inadequate targeting hinder their effectiveness. Herein, we present a novel PROTAC prodrug, NFTP, designed for FOXM1 degradation, which leverages self-assembled peptides functionalized with an integrin α-6 ligand to enhance tumor targeting and proteolysis in vivo. NFTP effectively penetrates tumor cells, induces FOXM1 degradation, inhibits cancer cell survival and migration, and promotes apoptosis in vitro. In a 4T1 mouse xenograft model, NFTP demonstrated efficient FOXM1-targeted degradation, significant tumor growth inhibition, and low systemic toxicity. This self-assembling FOXM1 PROTAC platform demonstrates enhanced tumor-targeting precision and superior therapeutic performance in vivo, representing a promising paradigm shift in targeted cancer therapy.
蛋白酶靶向嵌合体（PROTACs）是癌症治疗中针对“不可成药”蛋白的一种有前景的策略。然而，诸如生物利用度差、细胞通透性有限和靶向不足等挑战阻碍了它们的有效性。在此，我们提出了一种新型PROTAC前药NFTP，其设计用于降解FOXM1，它利用用整合素α-6配体功能化的自组装肽来增强体内肿瘤靶向性和蛋白水解作用。NFTP能有效穿透肿瘤细胞，诱导FOXM1降解，抑制癌细胞存活和迁移，并在体外促进细胞凋亡。在4T1小鼠异种移植模型中，NFTP显示出高效的FOXM1靶向降解、显著的肿瘤生长抑制和低全身毒性。这种自组装的FOXM1 PROTAC平台在体内表现出增强的肿瘤靶向精度和卓越的治疗性能，代表了靶向癌症治疗中一个有前景的范式转变。
