A Chimeric SERM–Histone Deacetylase Inhibitor Approach to Breast Cancer Therapy

Authors

  • Hitisha K. Patel,

    1. Department of Medicinal Chemistry and Pharmacognosy, University of Illinois College of Pharmacy, UIC, 833 S. Wood St., Chicago, IL 60612-7231 (USA)
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    • These authors contributed equally to this work.

  • Marton I. Siklos,

    1. Department of Medicinal Chemistry and Pharmacognosy, University of Illinois College of Pharmacy, UIC, 833 S. Wood St., Chicago, IL 60612-7231 (USA)
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    • These authors contributed equally to this work.

  • Hazem Abdelkarim,

    1. Department of Medicinal Chemistry and Pharmacognosy, University of Illinois College of Pharmacy, UIC, 833 S. Wood St., Chicago, IL 60612-7231 (USA)
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  • Emma L. Mendonca,

    1. Department of Medicinal Chemistry and Pharmacognosy, University of Illinois College of Pharmacy, UIC, 833 S. Wood St., Chicago, IL 60612-7231 (USA)
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  • Aditya Vaidya,

    1. Department of Medicinal Chemistry and Pharmacognosy, University of Illinois College of Pharmacy, UIC, 833 S. Wood St., Chicago, IL 60612-7231 (USA)
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  • Dr. Pavel A. Petukhov,

    1. Department of Medicinal Chemistry and Pharmacognosy, University of Illinois College of Pharmacy, UIC, 833 S. Wood St., Chicago, IL 60612-7231 (USA)
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  • Dr. Gregory R. J. Thatcher

    Corresponding author
    1. Department of Medicinal Chemistry and Pharmacognosy, University of Illinois College of Pharmacy, UIC, 833 S. Wood St., Chicago, IL 60612-7231 (USA)
    • Department of Medicinal Chemistry and Pharmacognosy, University of Illinois College of Pharmacy, UIC, 833 S. Wood St., Chicago, IL 60612-7231 (USA)

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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.

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