Discovery and biological evaluation of novel CARM1/HDAC2 dual-targeting inhibitors with anti-prostate cancer agents

Abstract

Prostate cancer (PCa) is a clinically heterogeneous disease with a progressively increasing incidence. Concurrent inhibition of coactivator-associated arginine methyltransferase 1 (CARM1) and histone deacetylase 2 (HDAC2) could potentially be a novel strategy against PCa. Herein, we identified seven compounds simultaneously targeting CARM1 and HDAC2 through structure-based virtual screening. These compounds possessed potent inhibitory activities at the nanomolar level in vitro. Among them, CH-1 was the most active inhibitor which exhibited excellent and balanced inhibitory effects against both CARM1 (IC₅₀ = 3.71 ± 0.11 nM) and HDAC2 (IC₅₀ = 4.07 ± 0.25 nM). MD simulations presented that CH-1 could stably bind the active pockets of CARM1 and HDAC2. Notably, CH-1 exhibited strong anti-proliferative activity against multiple prostate-related tumour cells (IC₅₀ < 1 µM). In vivo, assessment indicated that CH-1 significantly inhibited tumour growth in a DU145 xenograft model. Collectively, CH-1 could be a promising drug candidate for PCa treatment.

Keywords:

• Prostate cancer
• CARM1
• HDAC2
• dual-targeting inhibitors
• structure-based virtual screening

Acknowledgements

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

Author contributions

JL, LY, and ZX contributed to the conception of the study. SL and YG performed experiments and acquired data. ZX, MMN, YZ, and WH performed statistical analysis. JL, LY, ZX, SL, and YG contributed significantly to manuscript preparation. All authors had contributed and approved the manuscript.

Ethical 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 Funding of Taizhou People’s Hospital (Taizhou, Jiangsu, China [Grant No. ZL202005 and QDJJ202101]).