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Development of novel Vitamin D Receptor-Coactivator Inhibitors.

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.

SUBMITTER: Sidhu PS

PROVIDER: S-EPMC4007349 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Development of novel Vitamin D Receptor-Coactivator Inhibitors.

Sidhu Preetpal S PS Nassif Nicholas N McCallum Megan M MM Teske Kelly K Feleke Belaynesh B Yuan Nina Y NY Nandhikonda Premchendar P Cook James M JM Singh Rakesh K RK Bikle Daniel D DD Arnold Leggy A LA

ACS medicinal chemistry letters 20140201 2

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 ...[more]

PMID: 24799995

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