Discovery of novel anaplastic lymphoma kinase (ALK) and histone deacetylase (HDAC) dual inhibitors exhibiting antiproliferative activity against non-small cell lung cancer

• Published in: Journal of enzyme inhibition and medicinal chemistry 2024-12, Vol.39 (1), p.2318645-2318645
• Main Authors: Wang, Kang-Li, Yeh, Tsung-Yu, Hsu, Pei-Chen, Wong, Tzu-Hsuan, Liu, Jia-Rong, Chern, Ji-Wang, Lin, Miao-Hsia, Yu, Chao-Wu
• Format: Article
• Language: English
• Subjects: ALK; Anaplastic Lymphoma Kinase; Animals; antimour; Antineoplastic Agents - chemistry; Benzimidazoles; Body weight; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - metabolism; Cell Line, Tumor; Cell Proliferation; HDAC; Histone deacetylase; Histone Deacetylase Inhibitors - pharmacology; Humans; Hydroxamic acid; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Mice; Mice, Nude; mutantresistance; Mutants; Non-small cell lung carcinoma; Protein Kinase Inhibitors - chemistry; Protein-tyrosine kinase; Small cell lung carcinoma; Tumor cell lines
• ISSN: 1475-6366; 1475-6374
• DOI: 10.1080/14756366.2024.2318645

A series of novel benzimidazole derivatives were designed and synthesised based on the structures of reported oral available ALK inhibitor and HDAC inhibitor, pracinostat. In enzymatic assays, compound , containing a 2-acyliminobenzimidazole moiety and hydroxamic acid side chain, could inhibit both ALK and HDAC6 (IC = 16 nM and 1.03 µM, respectively). Compound also inhibited various ALK mutants known to be involved in crizotinib resistance, including mutant L1196M (IC , 4.9 nM). Moreover, inhibited the proliferation of several cancer cell lines, including ALK-addicted H2228 cells. To evaluate its potential for treating cancers , was used in a human A549 xenograft model with BALB/c nude mice. At 20 mg/kg, inhibited tumour growth by 85% yet had a negligible effect on mean body weight. These results suggest a attracting route for the further research and optimisation of dual ALK/HDAC inhibitors.