Development of Novel Vitamin D Receptor-Coactivator Inhibitors

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2014 May 7

PMID 24799995

Citations 12

Authors

Preetpal S Sidhu

Nicholas Nassif

Megan M McCallum

Kelly Teske

Belaynesh Feleke

Nina Y Yuan

Premchendar Nandhikonda

James M Cook

Rakesh K Singh

Daniel D Bikle

Leggy A Arnold

Affiliations

Soon will be listed here.

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)D activated gene transcription. In addition, PS121912 induced apoptosis in HL-60.

Citing Articles

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Enantioselective synthesis of α-tetrasubstituted (1-indolizinyl) (diaryl)-methanamines chiral phosphoric acid catalysis.

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