2. Academic Validation
  3. Development of novel Vitamin D Receptor-Coactivator Inhibitors

Development of novel Vitamin D Receptor-Coactivator Inhibitors

  • ACS Med Chem Lett. 2014 Feb 13;5(2):199-204. doi: 10.1021/ml400462j.
Preetpal S Sidhu 1,  Nicholas Nassif 1,  Megan M McCallum 1,  Kelly Teske 1,  Belaynesh Feleke 1,  Nina Y Yuan 1,  Premchendar Nandhikonda 1,  James M Cook 1,  Rakesh K Singh 2,  Daniel D Bikle 3,  Leggy A Arnold 1
Affiliations

Affiliations

  • 1 Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, WI 53211, USA.
  • 2 Molecular Therapeutics Laboratory, Program in Women's Oncology, Department of Obstetrics and Gynecology, Woman and Infant's Hospital of Rhode Island, Alpert Medical School of, Brown University, Provence, Rhode Island, USA.
  • 3 Endocrine Research Unit, Department of Medicine, Veterans Affairs Medical Center, San Francisco, CA 94121, USA.
PMID: 24799995 DOI: 10.1021/ml400462j
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.

Keywords

3-indolylmethanamines; CAMP; CYP24A1; HL60; VDR; Vitamin D receptor; apoptosis; fluorescence polarization; high throughput screening; steroid receptor coactivator.

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