Open AccessDevelopment of Novel Vitamin D Receptor–Coactivator Inhibitors
Author(s) -
Preetpal S. Sidhu,
Nicholas D. Nassif,
Megan M. McCallum,
Kelly A. Teske,
Belaynesh Feleke,
Nina Y. Yuan,
Premchendar Nandhikonda,
James M. Cook,
Rakesh K. Singh,
Daniel D. Bikle
Publication year - 2014
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/ml400462j
Subject(s) - calcitriol receptor , coactivator , nuclear receptor , nuclear receptor coactivator 3 , nuclear receptor coactivator 2 , transcription factor , receptor , chemistry , microbiology and biotechnology , nuclear receptor coactivator 1 , transcription (linguistics) , cancer research , biology , biochemistry , gene , linguistics , philosophy
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) 2 D 3 activated gene transcription. In addition, PS121912 induced apoptosis in HL-60.