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 <b>3b</b>, 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 <b>3b</b> also inhibited various ALK mutants known to be involved in crizotinib resistance, including mutant L1196M (IC₅₀, 4.9 nM). Moreover, <b>3b</b> inhibited the proliferation of several cancer cell lines, including ALK-addicted H2228 cells. To evaluate its potential for treating cancers <i>in vivo</i>, <b>3b</b> was used in a human A549 xenograft model with BALB/c nude mice. At 20 mg/kg, <b>3b</b> 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.