c-ros 致癌基因 1 (ROS1) 是一种致癌驱动因素，已知在过度激活时会诱发非小细胞肺癌 (NSCLC)，特别是通过形成融合蛋白。传统的靶向治疗侧重于用 ROS 1 抑制剂抑制 ROS1 活性来控制癌症进展。然而，一种涉及蛋白质降解剂设计的新策略提供了一种更有效的方法，通过完全降解ROS1融合癌蛋白，从而有效阻断其激酶活性并增强抗肿瘤潜力。利用PROTAC技术，通过分子对接和合理设计，我们报告了第一个ROS1特异性PROTAC，SIAIS039。该降解剂可有效靶向工程化 Ba/F3 细胞和 HCC78 细胞中的多种 ROS1 融合癌蛋白（CD74-ROS1、SDC4-ROS1 和 SLC34A2-ROS1），证明对 ROS1 融合驱动的癌细胞具有抗肿瘤作用。它抑制细胞增殖，诱导细胞周期停滞和细胞凋亡，并抑制克隆形成。 SIAIS039的抗肿瘤疗效超过两种已批准药物克唑替尼和恩曲替尼，并与包括劳拉替尼和他曲替尼在内的顶级抑制剂相媲美。机理研究证实039诱导的降解需要ROS1配体和E3泛素连接酶的参与，并涉及蛋白酶体和泛素化。此外，039在小鼠异种移植模型中表现出优异的口服生物利用度，凸显了其临床应用潜力。总之，我们的研究通过靶向降解ROS1融合癌蛋白，为ROS1融合阳性NSCLC提供了一种有前途的新颖治疗策略，为进一步开发PROTAC奠定了基础，并为ROS1融合阳性NSCLC患者带来了希望。版权所有©2024爱思唯尔公司保留所有权利。

The c-ros oncogene 1 (ROS1), an oncogenic driver, is known to induce non-small cell lung cancer (NSCLC) when overactivated, particularly through the formation of fusion proteins. Traditional targeted therapies focus on inhibiting ROS1 activity with ROS 1 inhibitors to manage cancer progression. However, a new strategy involving the design of protein degraders offers a more potent approach by completely degrading ROS1 fusion oncoproteins, thereby effectively blocking their kinase activity and enhancing anti-tumour potential. Utilizing PROteolysis-TArgeting Chimera (PROTAC) technology and informed by molecular docking and rational design, we report the first ROS1-specific PROTAC, SIAIS039. This degrader effectively targets multiple ROS1 fusion oncoproteins (CD74-ROS1, SDC4-ROS1 and SLC34A2-ROS1) in engineered Ba/F3 cells and HCC78 cells, demonstrating anti-tumour effects against ROS1 fusion-driven cancer cells. It suppresses cell proliferation, induces cell cycle arrest, and apoptosis, and inhibits clonogenicity. The anti-tumour efficacy of SIAIS039 surpasses two approved drugs, crizotinib and entrectinib, and matches that of the top inhibitors, including lorlatinib and taletrectinib. Mechanistic studies confirm that the degradation induced by 039 requires the participation of ROS1 ligands and E3 ubiquitin ligases, and involves the proteasome and ubiquitination. In addition, 039 exhibited excellent oral bioavailability in a mouse xenograft model, highlighting its potential for clinical application. In conclusion, our study presents a promising and novel therapeutic strategy for ROS1 fusion-positive NSCLC by targeting ROS1 fusion oncoproteins for degradation, laying the foundation for the development of further PROTAC and offering hope for patients with ROS1 fusion-positive NSCLC.Copyright © 2024 Elsevier Inc. All rights reserved.