Discovery of novel and potent dual-targeting AXL/HDAC2 inhibitors for colorectal cancer treatment via structure-based pharmacophore modelling, virtual screening, and molecular docking, molecular dynamics simulation studies, and biological evaluation

Abstract

Colorectal cancer (CRC) is one of the most common cancers worldwide. Nowadays, owing to the complex mechanism of tumorigenesis, simultaneous inhibition of multiple targets is an important anticancer strategy. Recent studies have demonstrated receptor tyrosine kinase AXL (AXL) and histone deacetylase 2 (HDAC2) are closely associated with colorectal cancer. Herein, we identified five hit compounds concurrently targeting AXL and HDAC2 using virtual screening. Inhibitory experiments revealed these hit compounds potently inhibited AXL and HDAC2 in the nanomolar range. Among them, Hit-3 showed the strongest inhibitory effects which were better than that of the positive control groups. Additionally, MD assays showed that Hit-3 could bind stably to the AXL and HDAC2 active pockets. Further MTT assays demonstrated that Hit-3 showed potent anti-proliferative activity. Most importantly, Hit-3 exhibited significant in vivo antitumor efficacy in xenograft models. Collectively, this study is the first discovery of dual-targeting AXL/HDAC2 inhibitors for colorectal cancer treatment.

Keywords:

• Colorectal cancer
• receptor tyrosine kinase AXL
• histone deacetylase 2
• dual-targeting AXL/HDAC2 inhibitor
• structure-based pharmacophore modelling

Acknowledgements

We gratefully acknowledge the support from the Taizhou People’s Hospital.

Authors contributions

YZ, HH and XQ contributed to the conception of the study. XW and MMN performed experiments and acquired data. XQ, SC, XW and MMN performed statistical analysis. YZ, HH, XQ, XW and MMN contributed significantly to manuscript preparation. All authors had contributed and approved the manuscript.

Ethics statement

All experimental protocols were reviewed and approved by the Animal Ethics Committee of China Pharmaceutical University.

Disclosure statement

The authors report no conflicts of interest.

Additional information

Funding

This work was supported by Huai’an Science and Technology Bureau (HAB202210), and Jiangsu Pharmaceutical Association-CHIATAI TIANQING Hospital Pharmacy Research Fund Program (Q202239).