Discovery of novel benzohydroxamate-based histone deacetylase 6 (HDAC6) inhibitors with the ability to potentiate anti-PD-L1 immunotherapy in melanoma.

In this study, a novel series of histone deacetylases 6 (HDAC6) inhibitors containing polycyclic aromatic rings were discovered and evaluated for their pharmacological activities. The most potent compound exhibited high HDAC6 inhibitory activity (IC = 261 nM) and excellent HDAC6 selectivity (SI = 109 for HDAC6 over HDAC3). also showed decent antiproliferative activity with IC of 7.37-21.84 μM against four cancer cell lines, comparable to that of tubastatin A (average IC = 6.10 μM). Further mechanism studies revealed that efficiently induced apoptosis and S-phase arrest in B16-F10 cells. In addition, markedly increased the expression of acetylated-α-tubulin both and , without affecting the levels of acetylated-H3 (marker of HDAC1 inhibition). Furthermore, (80 mg/kg) exhibited moderate antitumor efficacy in a melanoma tumour model with a tumour growth inhibition (TGI) of 32.9%, comparable to that (TGI = 31.3%) of tubastatin A. Importantly, the combination of with NP19 (a small molecule PD-L1 inhibitor discovered by us before) decreased tumour burden substantially (TGI% = 60.1%) as compared to monotherapy groups. Moreover, the combination of with NP19 enhanced the anti-tumour immune response, mediated by a decrease of PD-L1 expression levels and increased infiltration of anti-tumour CD8 T cells in tumour tissues. Collectively, represents a novel HDAC6 inhibitor deserving further investigation as a potential anti-cancer agent.