Histone Deacetylase 6 (HDAC6) is an essential regulator of histone acetylation processes, exerting influence on a multitude of cellular functions such as cell motility, endocytosis, autophagy, apoptosis, and protein trafficking through its deacetylation activity. The significant implications of HDAC6 in diseases such as cancer, neurodegenerative disorders, and immune disorders have motivated extensive investigation into the development of specific inhibitors targeting this enzyme for therapeutic purposes. Single targeting drugs carry the risk of inducing drug resistance, thus prompting exploration of dual targeting therapy which offers the potential to impact multiple signaling pathways simultaneously, thereby lowering the likelihood of resistance development. While pharmacological studies have exhibited promise in combined therapy involving HDAC6, challenges related to potential drug interactions exist. In response to these challenges, researchers are investigating HDAC6 hybrid molecules which enable the concomitant targeting of HDAC6 and other key proteins, thus enhancing treatment efficacy while mitigating side effects and reducing the risk of resistance compared to traditional combination therapies. The published design strategies for dual targeting inhibitors of HDAC6 are summarized and discussed in this review. This will provide some valuable insights into more novel HDAC6 dual targeting inhibitors to meet the urgent need for innovative therapies in oncology and other related fields.

Liver cancer exhibits a high degree of heterogeneity and involves intricate mechanisms. Recent research has revealed the significant role of histone lysine methylation and acetylation in the epigenetic regulation of liver cancer development. In this study, five inhibitors capable of targeting both histone lysine methyltransferase nuclear receptor-binding SET domain 2 (NSD2) and histone deacetylase 2 (HDAC2) were identified using a structure-based virtual screening approach. Notably, DT-NH-1 displayed a potent inhibition of NSD2 (IC50 = 0.08 ± 0.03 μM) and HDAC2 (IC50 = 5.24 ± 0.87 nM). DT-NH-1 also demonstrated a strong anti-proliferative activity against various liver cancer cell lines, particularly HepG2 cells, and exhibited a high level of biological safety. In an experimental xenograft model involving HepG2 cells, DT-NH-1 showed a significant reduction in tumour growth. Consequently, these findings indicate that DT-NH-1 will be a promising lead compound for the treatment of liver cancer with epigenetic dual-target inhibitors.

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.