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Updated: Aug 11, 2026
Assays for Validating Histone Acetyltransferase Inhibitors
Published on: August 6, 2020
A trifluoromethyl quinazoline inhibits hepatocellular carcinoma proliferation through HDAC1 binding and multi-target
Shimei Wang1, Xudong Cui1,2, Gang Yu3,4
1Department of Infectious Disease, The Fourth Hospital of Harbin Medical University, Harbin 150001, P.R. China.
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.
Insights
A novel compound, KZL-064, effectively inhibits hepatocellular carcinoma (HCC) growth and metastasis in preclinical models. Its multi-target mechanism, involving histone deacetylase 1 (HDAC1), offers a promising new therapeutic strategy for HCC.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Hepatocellular carcinoma (HCC) presents significant therapeutic challenges due to drug resistance, recurrence, and poor patient outcomes.
- Development of novel anticancer agents with well-defined mechanisms of action is crucial for improving HCC treatment efficacy.
Purpose of the Study:
- To identify and characterize a novel compound, KZL-064, as a potential therapeutic agent for hepatocellular carcinoma.
- To elucidate the molecular targets and mechanisms underlying the anti-cancer effects of KZL-064.
Main Methods:
- In vitro assays assessing cell proliferation, migration, invasion, apoptosis, and cell cycle.
- In vivo efficacy studies using MHCC97-H xenograft mouse models.
- Computational methods including virtual screening and molecular docking.
- Biochemical assays such as cellular thermal shift assay (CETSA) and biologic layer interferometer (BLI) to identify direct molecular targets.
Main Results:
- KZL-064 demonstrated significant inhibition of HCC cell proliferation, migration, and invasion, while also inducing apoptosis and G2/M cell cycle arrest.
- Oral administration of KZL-064 in xenograft mice achieved tumor suppression comparable to sorafenib, with no significant observed toxicity.
- Histone deacetylase 1 (HDAC1) was identified as a direct binding target of KZL-064.
- HDAC1 knockdown partially affected apoptosis and cell cycle progression but did not abolish the anti-migratory/invasive effects or overall efficacy of KZL-064.
Conclusions:
- KZL-064 is a potent inhibitor of hepatocellular carcinoma with multi-target mechanisms, including engagement of HDAC1 and p53-associated apoptotic pathways.
- The compound exhibits promising anti-cancer activity and a favorable safety profile in preclinical models, positioning it as a potential lead candidate for HCC therapy.
- These findings provide a conceptual framework for developing novel HCC therapies targeting multiple molecular pathways.
