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

Authors

Shimei Wang, Xudong Cui, Gang Yu, Xinwei Wan, Shinan Wei, Jia Yu, Sha Cheng, Dawei Zhang, Tomii Ayaka, Xiaoren Wang, Wanru Han, Bixue Xu, Heng Luo, Lei Yu

Published in

iScience. Volume 29. Issue 8. Pages 117037. Aug 21, 2026. Epub Jul 31, 2026.

Abstract

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.

PMID:
42572611
Bibliographic data and abstract were imported from PubMed on 10 Aug 2026.

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