清华大学饶燏团队研制了抑制与降解相结合的双靶双机制设计策略。相关研究成果于2024年12月2日发表在《美国化学会杂志》。

胶质母细胞瘤是一种高度侵袭性的脑肿瘤，缺乏有效的治疗方法，5年生存率低。新疗法的紧迫性是显而易见的。雷帕霉素（mTOR）和G1至S期转换1基因（GSPT1）的哺乳动物靶点在胶质母细胞瘤中过表达，调节重要的细胞功能。

目前的mTOR抑制剂在临床疗效和耐药性方面面临挑战。同样，GSPT1靶向疗法在胶质母细胞瘤的临床试验中也没有进展。研究表明，将mTOR抑制与GSPT1降解相结合可以克服耐药性并提高疗效。

研究人员提出了对不同蛋白质联合实施抑制和降解的概念，将抑制剂和降解剂的特性整合到同一分子中。引入一种新型双功能分子，YB-3–17，可强烈抑制mTOR并选择性降解GSPT1。

作为概念验证研究的工具化合物，YB-3-17可提高选择性，避免脱靶效应，并选择性诱导GSPT1降解和mTOR抑制，与独立疗法相比，在肿瘤细胞系中显示出更优的疗效。RNA-seq分析突出了YB-3-17优于mTOR抑制剂治疗的优势。

YB-3-17可以安全有效地抑制小鼠的肿瘤生长，为胶质母细胞瘤的精确治疗提供了有前景的方向，代表了首次尝试将mTOR抑制与GSPT1降解相结合。

该项工作还表明，从概念上讲，有可能成功地将小分子抑制剂和降解剂的特性结合成一个分子，从而一举两得。

附：英文原文

Title: A Dual-Target and Dual-Mechanism Design Strategy by Combining Inhibition and Degradation Together

Author: Yongbo Liu, Xiuyun Sun, Qianlong Liu, Chi Han, Yu Rao

Issue&Volume: December 2, 2024

Abstract: Glioblastoma, a highly aggressive brain tumor, lacks effective treatment with low 5 year survival rates. Urgency for new therapies is evident. Mammalian targets of rapamycin (mTOR) and G1 to S phase transition 1 gene (GSPT1) are overexpressed in glioblastoma, regulating vital cellular functions. Current mTOR inhibitors face challenges in clinical efficacy and drug resistance. Similarly, GSPT1-targeting therapies have not progressed of glioblastoma in clinical trials. Research studies suggested that combining mTOR inhibition with GSPT1 degradation may overcome resistance and enhance efficacy. We propose the concept of jointly implementing inhibition and degradation on different proteins, integrating the properties of inhibitors and degraders into the same molecule. Introducing YB-3–17, a novel bifunctional molecule, robustly inhibits mTOR and selectively degrades GSPT1. As a tool compound for proof-of-concept studies, YB-3–17 sharpens selectivity, avoiding off-target effects, and selectively induces GSPT1 degradation and mTOR inhibition, showing superior efficacy in tumor cell lines compared to that of standalone therapies. RNA-seq analysis highlights the advantages of YB-3-17 over mTOR inhibitor treatment. YB-3–17 can safely and effectively inhibit tumor growth in mice, offering a promising direction for precision treatment of glioblastoma, representing the first attempt to combine mTOR inhibition with GSPT1 degradation. This work also demonstrates that it is conceptually possible to successfully combine the properties of small molecule inhibitors and degraders into a single molecule, killing two birds with one stone.

DOI: 10.1021/jacs.4c11930

Source: https://pubs.acs.org/doi/abs/10.1021/jacs.4c11930