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Repositioning HDAC Inhibitors for Glioma Treatment: Synthesis and Biological Evaluation
Luciana Costa Furtado1,2, Karoline de Barros Waitman3, Nuno A T F Silva3
1Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, Avenida Professor Lineu Prestes 1524, 05508-000 São Paulo, Brazil.
Abstract:
Gliomas are a type of brain tumor associated with poor patient prognosis, with current treatment, surgical resection when feasible, followed by radiotherapy and chemotherapy (Temozolomide), yielding a median survival of approximately 15 months. In light of the urgent need for more effective therapies, histone deacetylases (HDACs) have emerged as promising targets, given their differential expression across tumor types and disease grades. Although HDAC inhibitors are well established in the treatment of hematological malignancies, their potential is now being explored in solid tumors, including glioblastoma (GBM). In this study, hydroxamate-based (3a) and benzamide-based (6a) HDAC inhibitors were synthesized and evaluated in glioma cell lines and glioblastoma stem cells (GSC). Treatment with these inhibitors resulted in cell cycle alterations, increased SubG1 populations, and enhanced apoptosis, particularly with compound 3a. Notably, 6a demonstrated greater potency in GSCs. The observed cytotoxic effects were linked to selective inhibition of HDAC6 by 3a and HDAC1/3 by 6a, as confirmed through enzymatic assays and further supported by molecular docking and molecular dynamics (MD) simulations. In silico analyses suggest that both compounds possess favorable pharmacokinetic profiles, underscoring their potential as promising candidates for glioma therapy and paving the way for future drug development in this field.
Insights
New HDAC inhibitors show promise for treating brain tumors like gliomas. Compound 3a and 6a demonstrated effectiveness in glioma cells and stem cells, offering potential for improved patient outcomes.
Area of Science:
- Oncology
- Neuro-oncology
- Medicinal Chemistry
Background:
- Gliomas, particularly glioblastoma (GBM), have poor prognoses with current treatments.
- Histone deacetylases (HDACs) are emerging targets for cancer therapy, with inhibitors established for hematological malignancies.
- Exploring HDAC inhibitors for solid tumors like gliomas is a critical area of research.
Purpose of the Study:
- To synthesize and evaluate novel hydroxamate-based (3a) and benzamide-based (6a) HDAC inhibitors.
- To assess the efficacy of these compounds in glioma cell lines and glioblastoma stem cells (GSCs).
- To elucidate the mechanism of action and pharmacokinetic profiles of the synthesized HDAC inhibitors.
Main Methods:
- Synthesis of hydroxamate-based (3a) and benzamide-based (6a) HDAC inhibitors.
- In vitro evaluation in glioma cell lines and GSCs, assessing cell cycle, apoptosis, and cytotoxicity.
- Enzymatic assays, molecular docking, and molecular dynamics simulations to confirm target inhibition and analyze pharmacokinetics.
Main Results:
- Both compounds induced cell cycle arrest, increased SubG1 populations, and enhanced apoptosis in glioma cells.
- Compound 3a showed significant effects, linked to selective HDAC6 inhibition.
- Compound 6a demonstrated greater potency in GSCs, associated with HDAC1/3 inhibition.
- In silico analyses indicated favorable pharmacokinetic profiles for both compounds.
Conclusions:
- Novel HDAC inhibitors 3a and 6a exhibit potent anti-glioma activity.
- Selective inhibition of specific HDACs (HDAC6 by 3a, HDAC1/3 by 6a) underlies their cytotoxic effects.
- These compounds represent promising candidates for future glioma therapeutic development.
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