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Updated: Dec 13, 2025
Assays for Validating Histone Acetyltransferase Inhibitors
Published on: August 6, 2020
Discovery of Novel c-Mesenchymal-Epithelia transition factor and histone deacetylase dual inhibitors
Hao Hu1, Fei Chen1, Yuhong Dong1
1Key Laboratory of Structure-Based Drug Design and Discovery. Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, PR China.
Abstract:
Clinically, a single agent that simultaneously inhibits multiple targets has been widely used in cancer treatment to overcome complicated dose design and anti-cancer resistance. Inspired by the synergistic effects between c-Met and HDAC in tumor development, a novel series of c-Met/HDAC bifunctional inhibitors was designed and synthesized by merging the pharmacophores of HDAC inhibitor into a c-Met inhibitor. All the target compounds were evaluated for their biological activity, the most potent compound, 14x, exhibited strong inhibition against HDAC1 with an IC50 of 18.49 nM and remarkable inhibitory activity against c-Met with an IC50 of 5.40 nM, respectively. In addition, 14x efficiently inhibited the proliferation of HCT-116, MCF-7 and A549 cell lines with IC50 values of 0.22 μM, 1.59 μM and 0.22 μM, respectively, which were superior to the reference compounds Cabozantinib and SAHA. Futhermore, 14x induced apoptosis and cause cell cycle arrest in G2/M phase. Docking experiments on c-Met and HDAC enzymes revealed the key interactions between 14x with the target protein. These results indicated that 14x was a potent dual c-Met/HDAC inhibitor and deserved for further investigation.
Insights
A novel bifunctional inhibitor, 14x, simultaneously targets c-Met and HDAC enzymes, showing potent anti-cancer activity. This dual-action approach offers a promising strategy for cancer treatment, overcoming resistance and simplifying drug design.
Area of Science:
- Medicinal Chemistry
- Oncology
- Molecular Biology
Background:
- Simultaneous inhibition of multiple targets is crucial for effective cancer therapy, addressing drug resistance and complex dosing.
- Synergistic roles of c-Met and Histone Deacetylase (HDAC) in tumor progression necessitate novel therapeutic strategies.
- Existing treatments often face challenges with resistance and require intricate dosing regimens.
Purpose of the Study:
- To design and synthesize novel c-Met/HDAC bifunctional inhibitors.
- To evaluate the biological activity and anti-cancer potential of these novel compounds.
- To investigate the molecular interactions of the lead compound with its targets.
Main Methods:
- Synthesis of novel c-Met/HDAC bifunctional inhibitors by merging pharmacophores.
- In vitro biological activity assays to determine IC50 values against HDAC1 and c-Met.
- Cell proliferation assays using HCT-116, MCF-7, and A549 cancer cell lines.
- Apoptosis induction and cell cycle analysis.
- Molecular docking studies with c-Met and HDAC enzymes.
Main Results:
- Compound 14x demonstrated potent inhibition against HDAC1 (IC50 = 18.49 nM) and c-Met (IC50 = 5.40 nM).
- 14x significantly inhibited proliferation in HCT-116 (IC50 = 0.22 μM), MCF-7 (IC50 = 1.59 μM), and A549 (IC50 = 0.22 μM) cell lines, outperforming reference drugs.
- 14x induced apoptosis and G2/M cell cycle arrest, confirmed by docking studies revealing key interactions.
Conclusions:
- Compound 14x is a potent dual inhibitor of c-Met and HDAC.
- The bifunctional inhibitor exhibits significant anti-cancer activity and warrants further investigation for clinical application.
- This study highlights the potential of dual-target inhibitors in cancer therapy.
