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
  • 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: [email protected].
  • 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: [email protected].
  • 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: [email protected].
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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