Breast cancer mortality still remains high and it is second only to lung cancer in women. Estrogen receptor (ER) antagonists and selective estrogen receptor modulators (SERMs) such as tamoxifen bind the receptor at the same site as estrogen (E2); however, with a binding profile that is profoundly different In the case of tam-ER complex, the outward folding of the helix 12 (H12) results in solvent exposer of the methyl groups which allows for modification without disrupting the binding affinity as much. Also, alongside genetic alteration of DNA, non-mutated DNA misregulation is a crime partner in cancer development. An imbalance in histone acetyl transferase (HAT) and histone deacetylase (HDAC) activities give rise to the development of wide variety of human cancers. To address this problem, small molecules have been designed as therapeutics to inhibit the activity of HDACs known as HDAC inhibitors (HDACi). The inhibitory mechanism of HDACis is through chelation of the Zn2+ ion that resides in the active site of the enzyme. So far, hydroxamic acid has been the most synthesized and characterized ZBG due to its strong chelation toward Zn2+ ion. However, this ZBG and current FDA approved HDACi have their own limitations including poor bio availability, lack of solid tumor penetration, and short half-life. To address these issues, we have replaced the hydroxamic acid with a bidentate heterocyclic ZBG. We expect that, by taking advantage of surface expressed ER receptor for selective uptake into ERα-positive cells, this design approach will furnish dual-activity SERM-HDACi conjugates to address the limitations of the current HDACi. Our preliminary data have demonstrated potent anticancer activity toward MCF-7 cell line with concentrations as low as 100 nM.

Design and synthesis of small molecule HDAC inhibitors equipped with ERα activity for selective targeting of the breast cancer

251st National Meeting (2016)

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