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Published on: August 10, 2017
Challenging triple negative breast cancer through HDAC6 selective inhibition: Novel cap-group identification,
Simona Barone1, Ivana Bello1, Anna Guadagni1
1Department of Pharmacy, Department of Excellence, 2023-2027, University of Naples Federico II, Via D. Montesano 49, 80131, Naples, Italy.
Abstract:
Triple negative breast cancer (TNBC) stands out among breast cancers subtypes for its high aggressiveness and invasiveness. Compelling new evidence pointed out the role of epigenetic modifications in TNBC, with recent studies demonstrating that approximately 30 % of human breast cancers could potentially benefit from histone deacetylase 6 (HDAC6) inhibitor therapy. We herein disclose a novel class of spiro-fused compounds acting as potent and selective HDAC6 inhibitors. Structure-based optimization led to derivatives 23c and 24c with high potency and selectivity towards HDAC6 in vitro and in cell-based settings. Following our observation that mRNA expression level of HDAC6 was significantly higher in MDA-MB-231, we have evaluated the effect of the compounds on cell viability. Moreover, we have unveiled for compounds 23c and 24c the involvement of the autophagic machinery in cell death induction. Scratch assay revealed for the newly conceived compounds a very potent effect on inhibiting the migration process in MDA-MB-231 cells. Our results underscore the key role of HDAC6 in TNBC progression, providing a solid groundwork to reshape TNBC therapy.
Insights
New spiro-fused compounds selectively inhibit histone deacetylase 6 (HDAC6), a key target in aggressive triple-negative breast cancer (TNBC). These potent inhibitors reduce cancer cell viability and migration, offering a promising new therapeutic strategy for TNBC.
Area of Science:
- Biochemistry
- Oncology
- Medicinal Chemistry
Background:
- Triple-negative breast cancer (TNBC) is highly aggressive and invasive.
- Epigenetic modifications play a role in TNBC progression.
- Histone deacetylase 6 (HDAC6) is a potential therapeutic target in breast cancer.
Purpose of the Study:
- To develop novel, potent, and selective HDAC6 inhibitors for TNBC therapy.
- To investigate the mechanism of action of these inhibitors in TNBC cells.
- To evaluate the therapeutic potential of these compounds in preclinical models.
Main Methods:
- Structure-based drug design and optimization of spiro-fused compounds.
- In vitro and cell-based assays to assess HDAC6 inhibition and selectivity.
- Cell viability, apoptosis, and migration assays using MDA-MB-231 TNBC cells.
- Investigation of autophagic machinery involvement in cell death.
Main Results:
- Novel spiro-fused compounds 23c and 24c were identified as potent and selective HDAC6 inhibitors.
- HDAC6 mRNA expression is elevated in MDA-MB-231 cells.
- Compounds 23c and 24c reduced cell viability and inhibited migration in MDA-MB-231 cells.
- Autophagic machinery is involved in the cell death induced by these compounds.
Conclusions:
- HDAC6 plays a critical role in TNBC progression.
- Novel spiro-fused HDAC6 inhibitors demonstrate significant preclinical efficacy.
- These findings provide a strong foundation for developing new HDAC6-targeted therapies for TNBC.
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