2. Academic Validation
  3. Discovery of a first-in-class protein degrader for the c-ros oncogene 1 (ROS1)

Discovery of a first-in-class protein degrader for the c-ros oncogene 1 (ROS1)

  • Bioorg Chem. 2024 Sep:150:107590. doi: 10.1016/j.bioorg.2024.107590.
Jiawen Yang 1,  Yifan Wu 2,  Qiaoliang Zhu 3,  Xiaojuan Qu 2,  Hongyue Ou 2,  Haixia Liu 4,  Yongqi Wei 3,  Di Ge 3,  Chunlai Lu 5,  Biao Jiang 6,  Xiaoling Song 7
Affiliations

Affiliations

  • 1 Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China; Shanghai Clinical Research and Trial Center, Shanghai 201210, China.
  • 2 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • 3 Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
  • 4 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China; School of Physical Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • 5 Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China. Electronic address: lu.chunlai@zs-hospital.sh.cn.
  • 6 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China; CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China. Electronic address: jiangbiao@shanghaitech.edu.cn.
  • 7 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China. Electronic address: songxl@shanghaitech.edu.cn.
PMID: 38955003 DOI: 10.1016/j.bioorg.2024.107590
Abstract

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.

Keywords

Lorlatinib; Non-small cell lung cancer; PROTAC; ROS1; Target protein degradation.

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