Discovery of the first irreversible small molecule inhibitors of the interaction between the vitamin D receptor and coactivators.

Journal of Medicinal Chemistry
Premchendar NandhikondaLeggy A Arnold

Abstract

The vitamin D receptor (VDR) is a nuclear hormone receptor that regulates cell proliferation, cell differentiation, and calcium homeostasis. The receptor is activated by vitamin D analogues that induce the disruption of VDR-corepressor binding and promote VDR-coactivator interactions. The interactions between VDR and coregulators are essential for VDR-mediated transcription. Small molecule inhibition of VDR-coregulator binding represents an alternative method to the traditional ligand-based approach in order to modulate the expression of VDR target genes. A high throughput fluorescence polarization screen that quantifies the inhibition of binding between VDR and a fluorescently labeled steroid receptor coactivator 2 peptide was applied to discover the new small molecule VDR-coactivator inhibitors, 3-indolylmethanamines. Structure-activity relationship studies with 3-indolylmethanamine analogues were used to determine their mode of VDR-binding and to produce the first VDR-selective and irreversible VDR-coactivator inhibitors with the ability to regulate the transcription of the human VDR target gene TRPV6.

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Citations

Nov 25, 2014·Nuclear Receptor Research·Kelly TeskeLeggy A Arnold
Aug 12, 2014·Cancer Chemotherapy and Pharmacology·Preetpal S SidhuLeggy A Arnold
Jan 18, 2016·European Journal of Medicinal Chemistry·Kelly A TeskeLeggy A Arnold
Jan 25, 2013·Medicinal Research Reviews·Laura Caboni, David G Lloyd
Apr 15, 2016·Assay and Drug Development Technologies·Matthew D HallMindy I Davis
May 14, 2014·Angewandte Chemie·Marcel ScheepstraLuc Brunsveld
Apr 28, 2016·Methods and Applications in Fluorescence·Matthew D HallNathan P Coussens
Dec 31, 2017·Bioorganic & Medicinal Chemistry Letters·Kelly A TeskeLeggy A Arnold
Jun 5, 2019·Molecular and Cellular Endocrinology·Kornelia J SkowronTerry W Moore
Feb 27, 2013·Journal of the American Chemical Society·Sascha FuchsLuc Brunsveld
Aug 22, 2017·ACS Combinatorial Science·Kelly A TeskeLeggy A Arnold
Jan 24, 2019·The Journal of Organic Chemistry·Hidemasa HikawaIsao Azumaya
May 7, 2014·ACS Medicinal Chemistry Letters·Preetpal S SidhuLeggy A Arnold

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