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Updated: May 8, 2026
Assays for Validating Histone Acetyltransferase Inhibitors
Published on: August 6, 2020
A chimeric SERM-histone deacetylase inhibitor approach to breast cancer therapy
Hitisha K Patel1, Marton I Siklos, Hazem Abdelkarim
1Department of Medicinal Chemistry and Pharmacognosy, University of Illinois College of Pharmacy, UIC, 833 S. Wood St., Chicago, IL 60612-7231 (USA).
Abstract:
Breast cancer remains a significant cause of death in women, and few therapeutic options exist for estrogen receptor negative (ER (-)) cancers. Epigenetic reactivation of target genes using histone deacetylase (HDAC) inhibitors has been proposed in ER (-) cancers to resensitize to therapy using selective estrogen receptor modulators (SERMs) that are effective in ER (+) cancer treatment. Based upon preliminary studies in ER (+) and ER (-) breast cancer cells treated with combinations of HDAC inhibitors and SERMs, hybrid drugs, termed SERMostats, were designed with computational guidance. Assay for inhibition of four type I HDAC isoforms and antagonism of estrogenic activity in two cell lines yielded a SERMostat with 1-3 μM potency across all targets. The superior hybrid caused significant cell death in ER (-) human breast cancer cells and elicited cell death at the same concentration as the parent SERM in combination treatment and at an earlier time point.
Insights
New hybrid drugs called SERMostats show promise for treating estrogen receptor-negative breast cancer. These compounds effectively kill cancer cells, offering a potential new therapeutic avenue for this difficult-to-treat disease.
Area of Science:
- Oncology
- Pharmacology
- Epigenetics
Background:
- Breast cancer, particularly estrogen receptor-negative (ER 2009(-)) types, presents limited therapeutic options and remains a significant cause of mortality in women.
- Histone deacetylase (HDAC) inhibitors are being investigated for their potential to epigenetically reactivate genes in ER 2009(-) cancers, aiming to restore sensitivity to selective estrogen receptor modulators (SERMs).
Purpose of the Study:
- To design and evaluate novel hybrid drugs, termed SERMostats, by combining HDAC inhibitors and SERMs for enhanced breast cancer treatment.
- To assess the efficacy of SERMostats in inhibiting HDAC isoforms and antagonizing estrogenic activity in both ER 2009(+) and ER 2009(-) breast cancer cells.
Main Methods:
- Computational guidance was employed to design hybrid SERMostat molecules.
- In vitro assays were conducted to determine the inhibitory potency of SERMostats against four type I HDAC isoforms.
- Estrogenic activity antagonism was evaluated in two distinct cell lines.
- Cell death induction in ER 2009(-) human breast cancer cells was assessed.
Main Results:
- A potent SERMostat was identified, demonstrating 1-3 0005μM potency across all evaluated HDAC targets and estrogenic activity antagonism.
- The lead SERMostat compound induced significant cell death in ER 2009(-) human breast cancer cells.
- This hybrid drug elicited cell death at concentrations comparable to the parent SERM in combination therapy but achieved this effect at an earlier time point.
Conclusions:
- The development of SERMostats represents a promising strategy for targeting ER 2009(-) breast cancer.
- These novel hybrid molecules demonstrate significant potential for inducing cancer cell death and overcoming therapeutic resistance in ER 2009(-) breast cancer.
- SERMostats offer a potential advancement in breast cancer therapy, particularly for patients with ER 2009(-) tumors.
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