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

Abstract

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.

GRAPHICAL ABSTRACT

Keywords:

• ALK
• HDAC
• antimour
• mutantresistance

Acknowledgements

The authors thank Hsuan-Chun Huang for help with HPLC sample analysis. The authors thank Pei-Shan Wu,Ting-An Chen, and Zong-Yu Yang for antiproliferation study, western blot assay, and IC₅₀ analysis.

Author contributions

The research work was done through the contributions of all authors. All authors have approved the final version of the manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This study was supported by MOST 110–2320-B-002 –010 -MY2 and grants from National Taiwan University to CWY. In the molecule modelling study, we thank to National Centre for High-performance Computing (NCHC) for providing computational and storage resources.