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Updated: Nov 5, 2025
Drug Repurposing Hypothesis Generation Using the "RE:fine Drugs" System
Published on: December 11, 2016
From Anti-infective Agents to Cancer Therapy: A Drug Repositioning Study Revealed a New Use for Nitrofuran
Gabriella Ortore1, Giulio Poli1, Adriano Martinelli1
1Department of Pharmacy, Pisa University, Pisa, Italy.
Background:
The progression of ovarian cancer seems to be related to HDAC1, HDAC3, and HDAC6 activity. A possible strategy for improving therapies for treating ovarian carcinoma, minimizing the preclinical screenings, is the repurposing of already approved pharmaceutical products as inhibitors of these enzymes.
Objective:
This work was aimed to implement a computational strategy for identifying new HDAC inhibitors for ovarian carcinoma treatment among approved drugs.
Method:
The CHEMBL database was used to construct training, test, and decoys sets for performing and validating HDAC1, HDAC3 and HDAC6 3D-QSAR models obtained by using the FLAP program. Docking and MD simulations were used in combination with the generated models to identify novel potential HDAC inhibitors. Cell viability assays and Western blot analyses were performed on normal and cancer cells for a direct evaluation of the anti-proliferative activity and an in vitro estimation of HDAC inhibition of the compounds selected through in silico screening.
Result:
The best quantitative prediction was obtained for the HDAC6 3D-QSAR model. The screening of approved drugs highlighted a new potential use as HDAC inhibitors for some compounds, in particular nitrofuran derivatives, usually known for their antibacterial activity and frequently used as antimicrobial adjuvant therapy in cancer treatment. Experimental evaluation of these derivatives highlighted a significant antiproliferative activity against cancer cell lines overexpressing HDAC6, and an increase in acetylated alpha-tubulin levels.
Conclusion:
Experimental results support the hypothesis of potential direct interaction of nitrofuran derivatives with HDACs. In addition to the possible repurposing of already approved drugs, this work suggests the nitro group as a new zinc-binding group, able to interact with the catalytic zinc ion of HDACs.
Insights
This study repurposed approved drugs as HDAC inhibitors for ovarian cancer. Nitrofuran derivatives showed significant antiproliferative activity against HDAC6-overexpressing cancer cells.
Area of Science:
- Biochemistry
- Computational Chemistry
- Oncology
Background:
- Ovarian cancer progression is linked to Histone Deacetylase (HDAC) activity, specifically HDAC1, HDAC3, and HDAC6.
- Repurposing existing drugs offers a strategy to develop novel ovarian carcinoma therapies and reduce preclinical screening.
- Targeting HDACs is a promising avenue for ovarian cancer treatment.
Purpose of the Study:
- To develop a computational strategy for identifying approved drugs that inhibit HDACs relevant to ovarian cancer.
- To discover new HDAC inhibitors for ovarian carcinoma treatment through drug repurposing.
Main Methods:
- Developed 3D-QSAR models for HDAC1, HDAC3, and HDAC6 using the CHEMBL database and FLAP program.
- Employed docking and molecular dynamics (MD) simulations to identify potential HDAC inhibitors.
- Validated computational findings with in vitro cell viability assays and Western blot analyses.
Main Results:
- The HDAC6 3D-QSAR model demonstrated the best predictive accuracy.
- Screening identified nitrofuran derivatives, known for antibacterial properties, as potential HDAC inhibitors.
- Nitrofuran derivatives exhibited significant antiproliferative effects on cancer cells overexpressing HDAC6 and increased acetylated alpha-tubulin.
Conclusions:
- Experimental data support the direct interaction of nitrofuran derivatives with HDACs.
- This research suggests repurposing approved drugs and highlights the nitro group as a novel zinc-binding group for HDAC inhibition.
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