A trifluoromethyl quinazoline inhibits hepatocellular carcinoma proliferation through HDAC1 binding and multi-target mechanisms.

Hepatocellular carcinoma (HCC) still has limitations such as tumor resistance, recurrence, and poor prognosis. Therefore, the development of anticancer drugs with mechanisms of action is of great significance for the treatment of HCC. In this study, we identified KZL-064, a 2-trifluoromethyl-4-aminoquinazoline derivative, which markedly inhibits HCC cell proliferation, migration, and invasion, induces apoptosis and G2/M arrest, and, in MHCC97-H xenograft mice, oral administration achieves tumor suppression comparable to that of sorafenib without significant toxicity. Through virtual screening, molecular docking, cellular thermal shift assay (CETSA), and biologic layer interferometer (BLI), we identified histone deacetylase 1 (HDAC1) as a direct binding target. Knockdown of HDAC1 partially attenuates pro-apoptotic and cell-cycle effects, yet does not impair anti-migratory/invasive activities nor completely abolish overall efficacy. Collectively, KZL-064 emerges as a promising lead, and its anti-proliferative action likely involves multi-target mechanisms engaging HDAC1 and p53-associated apoptotic signaling, offering a conceptual framework for HCC therapy.