title: 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)2D3activated gene transcription. In addition, PS121912 induced apoptosis in HL-60.
authors.affiliation: Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, WI 53211, USA.
authors.forename: Preetpal S
authors.initials: PS
authors.lastname: Sidhu
authors.affiliation: Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, WI 53211, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Nassif
authors.affiliation: Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, WI 53211, USA.
authors.forename: Megan M
authors.initials: MM
authors.lastname: McCallum
authors.affiliation: Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, WI 53211, USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: Teske
authors.affiliation: Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, WI 53211, USA.
authors.forename: Belaynesh
authors.initials: B
authors.lastname: Feleke
authors.affiliation: Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, WI 53211, USA.
authors.forename: Nina Y
authors.initials: NY
authors.lastname: Yuan
authors.affiliation: Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, WI 53211, USA.
authors.forename: Premchendar
authors.initials: P
authors.lastname: Nandhikonda
authors.affiliation: Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, WI 53211, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Cook
authors.affiliation: 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.
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Singh
authors.affiliation: Endocrine Research Unit, Department of Medicine, Veterans Affairs Medical Center, San Francisco, CA 94121, USA.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Bikle
authors.affiliation: Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, WI 53211, USA.
authors.forename: Leggy A
authors.initials: LA
authors.lastname: Arnold
keywords: 3-indolylmethanamines; CAMP; CYP24A1; HL60; VDR; Vitamin D receptor; apoptosis; fluorescence polarization; high throughput screening; steroid receptor coactivator