Nicholas Nassif - Development of Novel Vitamin D Receptor–Coactivator Inhibitors

Version 1

      Publication Details (including relevant citation   information):

      ACS Med. Chem. Lett., 2014, 5 (2), pp   199–204

    DOI: 10.1021/ml400462j

    Publication Date (Web): January 8, 2014

    Copyright © 2014 American Chemical Society

      Abstract:

        Nuclear receptor coregulators are master regulators of   transcription and selectively interact with the vitamin D   receptor (VDR) to modulate cell differentiation, cell   proliferation, and calcium homeostasis. Herein, we report the   syntheses and evaluation of highly potent and selective   VDR–coactivator inhibitors based on a recently identified   3-indolylmethanamine scaffold. The most active compound,   PS121912, selectively inhibited VDR-mediated transcription among   eight other nuclear receptors tested. PS121912 is also   selectively disrupting the binding between VDR and the third   nuclear receptor interaction domain of the coactivator SRC2.   Genetic studies revealed that PS121912 behaves like a VDR   antagonist by repressing 1,25-(OH)2D3    activated gene transcription. In addition, PS121912 induced   apoptosis in HL-60.

      Address (URL): http://pubs.acs.org/doi/abs/10.1021/ml400462j