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

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 3b, containing a 2-acyliminobenzimidazole moiety and hydroxamic acid side chain, could inhibit both ALK and HDAC6 (IC50 = 16 nM and 1.03 µM, respectively). Compound 3b also inhibited various ALK mutants known to be involved in crizotinib resistance, including mutant L1196M (IC50, 4.9 nM). Moreover, 3b inhibited the proliferation of several cancer cell lines, including ALK-addicted H2228 cells. To evaluate its potential for treating cancers in vivo, 3b was used in a human A549 xenograft model with BALB/c nude mice. At 20 mg/kg, 3b 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.基于已报道的口服ALK（Anaplastic Lymphoma Kinase，间变性淋巴瘤激酶）抑制剂与HDAC（Histone Deacetylase，组蛋白去乙酰化酶）抑制剂帕立诺司他（pracinostat）的结构，研究人员设计并合成了一系列新型苯并咪唑衍生物。在酶学实验中，带有2-酰基亚胺苯并咪唑基团与异羟肟酸侧链的化合物3b，可同时抑制ALK与HDAC6，半数抑制浓度（IC50）分别为16 nM与1.03 μM。化合物3b还可抑制多种与克唑替尼耐药相关的ALK突变体，包括L1196M突变体，其IC50值为4.9 nM。此外，化合物3b能够抑制多种癌细胞系的增殖，其中包括ALK依赖型H2228细胞系。为评估其体内抗肿瘤治疗潜力，研究人员采用BALB/c裸鼠构建人源A549异种移植瘤模型，并以化合物3b进行干预。在20 mg/kg的给药剂量下，化合物3b可抑制85%的肿瘤生长，且对小鼠平均体重无显著影响。上述研究结果为双靶点ALK/HDAC抑制剂的后续研究与优化提供了极具吸引力的研发路径。