The vitamin D receptor (VDR) belongs to the superfamily of nuclear receptors and transcribes genes responsible for metabolism, calcium homeostasis, cell proliferation, and cell differentiation. The regulation of VDR is mediated by endogenous secosteroid ligands, including 1,25-dihydroxyvitamin D3, and coregulator proteins, which have been identified as master regulators of transcription. In order to identify molecular probes to determine the biological functions of coregulators in respect to VDR-mediated transcription a high throughput screen (HTS) was carried out in collaboration with the National Institute of Health. The HTS identified different classes of compounds that modulate the interaction between VDR and coregulators. Herein, we present the discovery and synthesis of VDR-coregulator inhibitors. Using parallel chemistry, small molecule libraries were synthesized and characterized with a battery of biochemical assays. In addition, early stage preclinical in vitroassays were used for their characterization and to guide multiple rounds of computational design, synthesis and evaluation. A core isoindolone scaffold was identified with examples of highly selective low-micromolar inhibitors.Our current effort is focused on the development of these compounds into anticancer drugs. In contrast to the very successful nuclear receptor ligands tamoxifen and flutamide targeting the estrogen and androgen receptor, these inhibitors target VDR-coregulator interactions and inhibit the proliferation and differentiation of cancer cells. We hope that crystallographic data will be available in time to disclose the exact binding modes of these novel molecules. Overall, we will present a chemical approach to identify the role of coregulators including that of coactivator AIB1 (amplified in breast cancer-1) in concert VDR in cancer.

Discovery of transcriptional modulators that target the vitamin D receptor

247th National Meeting (2014)

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