2. Academic Validation
  3. Discovery of an ALK degrader for lorlatinib-resistant compound mutations

Discovery of an ALK degrader for lorlatinib-resistant compound mutations

  • Eur J Med Chem. 2025 Oct 15:296:117835. doi: 10.1016/j.ejmech.2025.117835.
Fei Gao 1,  Zhenhua Wu 1,  Anqi Lin 2,  Xinyu Wu 1,  Baoding Zhang 1,  Liqing Liu 1,  Yue Lu 1,  Shangshang Geng 2,  Zhen Huang 2,  Yiyu Chen 1,  Jianming Zhang 3,  Li Li 4,  Xianming Deng 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, 361102, China; State-province Joint Engineering Laboratory of Targeted Drugs from Natural Products, Xiamen University, Xiamen, 361102, China; Cancer Research Center of Xiamen University, Xiamen, 361102, China.
  • 2 State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, 361102, China.
  • 3 Institute of Translational Medicine, Zhangjiang Institute for Advanced Study, Shanghai Jiao Tong University, Shanghai, 200240, China. Electronic address: jzuc@sjtu.edu.cn.
  • 4 State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, 361102, China; State-province Joint Engineering Laboratory of Targeted Drugs from Natural Products, Xiamen University, Xiamen, 361102, China; Cancer Research Center of Xiamen University, Xiamen, 361102, China. Electronic address: lli@xmu.edu.cn.
  • 5 State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, 361102, China; State-province Joint Engineering Laboratory of Targeted Drugs from Natural Products, Xiamen University, Xiamen, 361102, China; Cancer Research Center of Xiamen University, Xiamen, 361102, China; Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, Xiamen University, Xiamen, 361003, China. Electronic address: xmdeng@xmu.edu.cn.
PMID: 40479896 DOI: 10.1016/j.ejmech.2025.117835
Abstract

Three generations of ALK tyrosine kinase inhibitor (ALK TKI) have achieved significant clinical success in the treatment of ALK rearranged non-small cell lung Cancer (NSCLC). However, the emergence of acquired mutations after sequential ALK TKI therapies poses significant challenges for Cancer treatment. Here we identified WZH-15-125 as a potent ALK inhibitor that can effectively override drug resistance, especially compound ALK mutations, including the highly refractory G1202R/L1196M mutation that is resistant to lorlatinib. By using WZH-15-125 as the warhead, we designed an ALK PROTAC molecule WZH-17-002 that can efficiently degrade ALK proteins with half maximal degradation concentration (DC50) values of 25 nM. Furthermore, WZH-17-002 suppresses the emergence of drug resistance and exhibits superior in vivo pharmacological efficacy than lorlatinib in ALK G1202R/L1196M xenograft mouse models. These findings suggest a potential strategy for overcoming resistance to ALK TKI therapies.

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