Novel biphenyl-based scaffold as potent and selective histone deacetylase 6 (HDAC6) inhibitors: Identification,...

A series of novel biphenyl-based scaffold derivatives were identified as selective histone deacetylase 6 (HDAC6) inhibitors through an in-house compound library screening approach. The biological evaluation indicated that most of target compounds exhibited moderate to good inhibitory activity and selectivity against HDAC6. Especially, compound C10 was identified as a potent and highly selective HDACs inhibitor, with HDAC1 IC₅₀ value of 3600 nM, HDAC6 IC₅₀ value of 23 nM, and the HDAC1/6 selectivity index of 157. Moreover, C10 displayed robust anti-proliferative activity, induced cancer cells apoptosis, increased the level of acetylated α-tubulin and inhibited cancer cells migration in vitro. C10 showed significant antitumor efficacy (TGI: 75%) in CT26 colon carcinoma xenograft model in mice with no considerable toxicity in vivo. More importantly, C10 could also activate antitumor immunity so as to synergistically exert antitumor effects in vivo. Overall, our findings have provided a new avenue for design, development and investigation into the mechanism underlying the antitumor efficacy of selective HDAC6 inhibitors.