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  3. Discovery of the first potent ROR1 degrader for the treatment of non-small cell lung cancer

Discovery of the first potent ROR1 degrader for the treatment of non-small cell lung cancer

  • Eur J Med Chem. 2025 Mar 15:286:117325. doi: 10.1016/j.ejmech.2025.117325.
Jinlin Li 1,  Lin Li 2,  Caiyun Hou 1,  Zhaodi Tian 2,  Yang Zhou 1,  Jinwei Zhang 2,  Xiaomei Ren 2,  Zhen Wang 2,  Weixue Huang 3,  Ke Ding 4,  Fengtao Zhou 5
Affiliations

Affiliations

  • 1 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MoE) of People's Republic of China, College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China.
  • 2 State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, China.
  • 3 State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, China. Electronic address: wxhuang@sioc.ac.cn.
  • 4 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MoE) of People's Republic of China, College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China; State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, China. Electronic address: dingk@sioc.ac.cn.
  • 5 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MoE) of People's Republic of China, College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China. Electronic address: fengtaozhou@jnu.edu.cn.
PMID: 39889450 DOI: 10.1016/j.ejmech.2025.117325
Abstract

ROR1 has been identified as a pseudokinase, functioning as an allosteric regulator in tumor progression. Aberrant overexpression of ROR1 has been observed in various malignancies, highlighting its potential as therapeutic target for Cancer therapy. Modulation of ROR1 by proteolysis targeting chimera degrader instead of traditional inhibitor could offer great efficiency in blocking its kinase-independent regulatory function. Here, we report the first potent ROR1 degraders constructed by connecting the E3 ligand to a ROR1 binder. One representative compound 11d exhibited remarkable efficacy in depleting ROR1 protein with a DC50 value of 40.88 nM and Dmax of 93.7 %. Mechanistic investigations illuminated that compound 11d triggers ROR1 protein degradation in a ubiquitin Proteasome system (UPS)-dependent manner. Additionally, compound 11d displayed a significantly enhanced ability to inhibit ROR1 signaling, induce Apoptosis, and suppress proliferation in lung cell lines compared to the warhead ROR1 binder. These findings underscore the substantial potential of ROR1 degrader for the treatment of non-small cell lung Cancer (NSCLC) cells.

Keywords

Apoptosis; NSCLC; PROTACs; Proliferation; Protein degradation; Pseudokinase; ROR1.

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