2. Academic Validation
  3. Discovery of CZY43 as a new small-molecule degrader of pseudokinase HER3

Discovery of CZY43 as a new small-molecule degrader of pseudokinase HER3

  • Eur J Med Chem. 2025 Mar 5:285:117258. doi: 10.1016/j.ejmech.2025.117258.
Zhiyuan Chen 1,  Rui He 2,  Shengjie Huang 2,  Yang Zhou 2,  Zhang Zhang 2,  Zhen Wang 3,  Ke Ding 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, #345 Lingling Rd, Shanghai, 200032, China; University of Chinese Academy of Sciences, No. 1 Yanxihu Road Huairou District, Beijing, 101408, China.
  • 2 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, College of Pharmacy, Jinan University, 855 Xingye Avenue East, Guangzhou, 511400, China.
  • 3 State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, #345 Lingling Rd, Shanghai, 200032, China; Ningbo Zhongke Creation Center of New Materials, Ningbo, 315000, China.
  • 4 State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, #345 Lingling Rd, Shanghai, 200032, China. Electronic address: dingk@sioc.ac.cn.
PMID: 39818014 DOI: 10.1016/j.ejmech.2025.117258
Abstract

The pseudokinase HER3 emerges as a promising anti-cancer target, especially for HER2-driven breast Cancer and EGFR-mediated non-small cell lung Cancer. However, it is challenging to target HER3 by ATP-competitive small molecules because HER3 is catalytically impaired. Herein, we report the discovery of a series of HER3 degraders by connecting a HER3 binder bosutinib with a hydrophobic tag adamantane. The optimal compound CZY43 effectively induced HER3 degradation in dose- and time-dependent manners in breast Cancer SKBR3 cells. Mechanistic studies revealed compound CZY43 to induce HER3 degradation via Autophagy. Importantly, compound CZY43 potently inhibited HER3-dependent signaling, Cancer cell growth and cell adhesion, and was more potent than bosutinib. This study further suggested that HER3 can be modulated by small-molecule degraders, and compound CZY43 can serve as a lead compound for further optimization.

Keywords

Autophagy; Breast cancer; HER3; Hydrophobic tag degrader; Pseudokinase.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-172091
    HER3 Inhibitor