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Updated: Oct 11, 2025
Assays for Validating Histone Acetyltransferase Inhibitors
Published on: August 6, 2020
Quinazoline-based hydroxamic acid derivatives as dual histone methylation and deacetylation inhibitors for potential
Haoting Zheng1, Qiuzi Dai1, Zigao Yuan2
1Department of Chemistry, Tsinghua University, Beijing 100084, PR China; National & Local United Engineering Lab for Personalized Anti-tumor Drugs, The State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Biology, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, Guangdong 518055, PR China.
Abstract:
Cancer is a common malignant disease with complex signaling networks, which means it is unmanageable to cancer therapy by using single classical targeted drug. Recently, dual- or multitarget drugs have emerged as a promising option for cancer therapies. Although many multifunctional compounds targeting HDAC have been validated, as far as we know, there is no molecule targeting GLP and HDAC synchronously. In the present work, we designed and synthesized a series of quinazoline-based hydroxamic acid derivatives as dual GLP and HDAC inhibitors. These hybrid compounds showed potent enzymatic inhibitory activities against GLP and HDAC1/6 with IC50 values in the nanomolar range of less than 190 nM. Furthermore, most of our compounds displayed significant broad spectrum cytotoxic activities apart from D3 and D8 against all the tested cancer cells with IC50 values less than 50 μM. D1, D6 and D7 showed more potent cytotoxic activities than D2, D4 and D5 in those cancer cells. Especially, compound D7 showed potent inhibitory potency activity against both GLP and HDAC1/6 with IC50 values of 1.3, 89, 13 nM. Besides, D7 exhibited the most potent antiproliferative activity against all the tested cancer cells. Further evaluations indicated that D7 could inhibit the methylation and deacetylation of H3K9 on protein level. Moreover, D7 could induce cancer cell apoptosis, G0/G1 cell cycle arrest, and partly block migration and invasion. All these thorough evaluations warranted D7 as a promising lead compound worth further optimization and development for cancer therapy.
Insights
Researchers developed novel dual inhibitors targeting GLP and HDAC for cancer therapy. Compound D7 demonstrated potent anti-cancer activity by inhibiting key cellular processes and inducing apoptosis, showing promise for future drug development.
Area of Science:
- Medicinal Chemistry
- Oncology
- Molecular Biology
Background:
- Cancer's complex signaling networks necessitate multitargeting drugs over single-agent therapies.
- While numerous HDAC inhibitors exist, no compounds simultaneously target GLP and HDAC.
- Dual-targeting strategies offer a promising avenue for overcoming cancer treatment limitations.
Purpose of the Study:
- To design and synthesize novel quinazoline-based hydroxamic acid derivatives as dual GLP and HDAC inhibitors.
- To evaluate the enzymatic inhibitory and cytotoxic activities of these compounds against cancer cells.
- To investigate the molecular mechanisms underlying the anti-cancer effects of the most potent compound.
Main Methods:
- Synthesis of quinazoline-based hydroxamic acid derivatives.
- Enzymatic assays to determine IC50 values for GLP and HDAC1/6 inhibition.
- In vitro cytotoxic assays against a panel of cancer cell lines.
- Western blot analysis to assess H3K9 methylation and deacetylation.
- Cell cycle analysis and apoptosis assays.
Main Results:
- Synthesized compounds exhibited potent dual inhibitory activity against GLP and HDAC1/6 (IC50 < 190 nM).
- Most compounds displayed significant broad-spectrum cytotoxic effects against tested cancer cells (IC50 < 50 μM).
- Compound D7 showed exceptional potency, inhibiting GLP and HDAC1/6 (IC50: 1.3, 89, 13 nM) and exhibiting strong antiproliferative activity.
- D7 inhibited H3K9 methylation/deacetylation, induced apoptosis, G0/G1 cell cycle arrest, and reduced migration/invasion.
Conclusions:
- The novel quinazoline-based hydroxamic acid derivatives are effective dual GLP and HDAC inhibitors.
- Compound D7 is a highly promising lead compound with broad-spectrum anti-cancer properties.
- D7 warrants further investigation and optimization for potential cancer therapeutic applications.
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