HDAC1/6-IN-3 is an effective HDAC inhibitor with significant inhibitory effects on HDAC1 (IC50= 1.1 nM) and HDAC6 (IC50= 2.7 nM). In HepG2 cells, it causes cell cycle arrest at the G0/G1 phase and induces apoptosis and pyroptosis. Furthermore, HDAC1/6-IN-3 demonstrates notable antitumor activity in HepG2 tumor xenograft models. This compound is applicable for cancer research, including studies on liver, lung, colon, and breast cancers.

HDAC1:1.1 nM

HDAC1/6-IN-3 (Compound 15a) displays remarkable inhibitory activity against several cancer cell lines, with IC50 values of 0.12 μM for HepG2, 0.53 μM for PC9, 1.12 μM for HCT116, and 3.12 μM for MCF7 cells over 72 hours. When administered at concentrations of 0.2-0.5 μM for 24 hours, it increases acetyl-H3 and H4 levels in HepG2 cells in a dose-dependent manner. Additionally, this compound inhibits colony formation in HepG2 cells at the same concentration range over 10-14 days. HDAC1/6-IN-3 also induces G0/G1 phase arrest in HepG2 cells, likely linked to the downregulation of CDK4 and Cyclin D1 proteins, at 0.2-0.5 μM over 24 hours. Furthermore, apoptosis in HepG2 cells is prompted by enhancing ROS production and DNA damage accumulation with 0.2-0.5 μM treatment over 48 hours. Finally, HDAC1/6-IN-3 triggers pyroptosis in HepG2 cells through caspase-3-mediated cleavage of GSDME at 0.2-0.5 μM over 24-48 hours.

HDAC1/6-IN-3 (Compound 15a), administered intraperitoneally at 10 mg/kg twice weekly for 3 weeks, exhibits significant antitumor activity with acceptable safety characteristics in the HepG2 xenograft model.