2. Academic Validation
  3. Design, synthesis and biological evaluation of ALK/HDAC dual-targeting agents

Design, synthesis and biological evaluation of ALK/HDAC dual-targeting agents

  • Bioorg Med Chem Lett. 2025 Dec 11:133:130495. doi: 10.1016/j.bmcl.2025.130495.
Ye Kong 1,  Shunda Li 2,  Xintong Xue 2,  Huiping Liu 3,  Ruiwei Fu 4,  Yan Gao 1,  Yingjie Zhang 5,  Xia Xue 6
Affiliations

Affiliations

  • 1 Department of Pharmacy, The Second Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, PR China.
  • 2 Department of Medicinal Chemistry, Shandong Key Laboratory of Druggability Optimization and Evaluation for Lead Compounds, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, PR China.
  • 3 School of Pharmacy, Yantai University, Yantai, Shandong, PR China.
  • 4 Cheeloo College of Medicine, Shandong University, Jinan, Shandong, PR China; People's Hospital of Xia Jin, Dezhou, Shandong, PR China.
  • 5 Department of Medicinal Chemistry, Shandong Key Laboratory of Druggability Optimization and Evaluation for Lead Compounds, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, PR China. Electronic address: [email protected].
  • 6 Department of Pharmacy, The Second Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, PR China. Electronic address: [email protected].
PMID: 41389892 DOI: 10.1016/j.bmcl.2025.130495
Abstract

Dual inhibition of ALK and HDACs might be an effective Cancer treatment approach. We designed and synthesized novel dual ALK and HDAC inhibitors using molecular hybridization and pharmacophore merging. In enzymatic assays, compound 19b showed dual inhibitory activity against ALK (ALK WT IC50 = 8.0 ± 1.2 nM) and HDACs (HeLa cell nuclear extract IC50 = 1.18 ± 0.22 μM). Notably, 19b exhibited ~5-fold greater inhibition than Staurosporine and approved ALK inhibitor Brigatinib against the ALK G1202R mutant. Additionally, 19b demonstrated strong activity in ALK-related neuroblastoma SK-N-BE2 cells, comparable to controls SAHA, MS275, and Brigatinib. In SK-N-BE2 cells, 19b treatment led to increased Apoptosis and G2/M arrest. Docking studies explained the potent dual inhibition by 19b. These findings support the promise of 19b as a dual ALK/HDAC Inhibitor for managing neuroblastoma, especially ALK-positive Cancer.

Keywords

Anaplastic lymphoma kinase (ALK); Dual inhibition; G1202R mutant; Histone deacetylase (HDAC); Neuroblastoma.

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