Modeling, synthesis and cell-based evaluation of pyridine-substituted analogs of CD3254 and fluorinated analogs of CBt-PMN as novel therapeutics.

Six pyridine analogs of (E)-3-(3-(1,2,3,4-tetrahydro-1,1,4,4,6-pentamethylnaphthalen-7-yl)-4-hydroxyphenyl)acrylic acid-or CD3254 (11)-in addition to two novel analogs of 1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1H-benzo[d][1,2,3]triazole-5-carboxylic acid (CBt-PMN or 23) were prepared and evaluated for selective retinoid-X-receptor (RXR) agonism alongside bexarotene (1), an FDA-approved drug for cutaneous T-cell lymphoma (CTCL). Treatment with 1 often elicits side-effects by disrupting or provoking other RXR-dependent nuclear receptors and cellular pathways. All analogs were assessed through modeling for their ability to bind RXR and then evaluated in human colon and kidney cells employing an RXR-RXR mammalian-2-hybrid (M2H) system and in an RXRE-controlled transcriptional assay.

Synergistic Activation of VDR-RXR Heterodimers by Vitamin D and Rexinoids in Human Kidney and Brain Cells.

The active form of vitamin D, 1,25-dihydroxyvitamin D (1,25D), binds to the vitamin D receptor (VDR) with high affinity. The VDR then heterodimerizes with the retinoid X receptor (RXR) and associates with vitamin D response elements (VDREs) to regulate the transcription of target genes. Bexarotene (Bex) is an RXR ligand (rexinoid) developed to treat cutaneous T-cell lymphoma and is a putative therapeutic for other diseases.

Rexinoids Induce Differential Gene Expression in Human Glioblastoma Cells and Protein-Protein Interactions in a Yeast Two-Hybrid System.

Rexinoids are compounds that bind to the rexinoid X receptor (RXR) to modulate gene expression and have been proposed as a new class of therapeutics to treat Alzheimer's disease. Different rexinoids will initiate downstream effects that can be quite marked even though such compounds can be structurally similar and have comparable RXR binding affinities. RXR can both homo- and heterodimerize, and these protein-protein interactions and subsequent transactivating potential lead to differential gene expression, depending on the RXR dimeric partner, additional cofactors recruited, and downstream transcription factors that are up- or downregulated.

The Role of Intestinal Cytochrome P450s in Vitamin D Metabolism.

Vitamin D hydroxylation in the liver/kidney results in conversion to its physiologically active form of 1,25-dihydroxyvitamin D [1,25(OH)D]. 1,25(OH)D controls gene expression through the nuclear vitamin D receptor (VDR) mainly expressed in intestinal epithelial cells. Cytochrome P450 (CYP) 24A1 is a catabolic enzyme expressed in the kidneys.

Development of Bexarotene Analogs for Treating Cutaneous T-Cell Lymphomas.

Bexarotene, a drug approved for treatment of cutaneous T-cell lymphoma (CTCL), is classified as a rexinoid by its ability to act as a retinoid X receptor (RXR) agonist with high specificity. Rexinoids are capable of inducing RXR homodimerization leading to the induction of apoptosis and inhibition of proliferation in human cancers. Numerous studies have shown that bexarotene is effective in reducing viability and proliferation in CTCL cell lines.