Target Validation Information
TTD ID	T34234
Target Name	Vitamin D3 receptor (VDR)
Type of Target	Successful
Drug Potency against Target	Calcipotriol	Drug Info	IC50 = 1.8 nM
	Ergocalciferol	Drug Info	IC50 = 1910 nM	[3]
	Paricalcitol	Drug Info	EC50 = 8.7 nM	[4]
	KSP-BCS-1-alpha-CHF2-1624F2-2	Drug Info	IC50 = 50 nM	[1]
	KSP-BCS-1-alpha-CHF2-20-epi-22-oxabishomo-26-OH	Drug Info	IC50 = 19.5 nM	[1]
Action against Disease Model	Calcipotriol	Drug Info	Bacterial infection might influence the clinical response of patients with immunological disorders including psoriasis to the therapeutic efficacies of immunosuppressive drugs, but few studies have been carried out to investigate the implication of bacterial superantigens. We evaluated the suppressive efficacies of betamethasone butyrate propionate, vitamin D3 derivatives, and cyclosporine against concanavalin A- or superantigen-induced proliferation of peripheral-blood mononuclear cells obtained from 18 healthy subjects. In vitro drug concentrations giving 50% inhibition (IC50s) of peripheral-blood mononuclear cell-proliferation stimulated with concanavalin A or streptococcal pyrogenic enterotoxin A were estimated. Concentrations of t uMor necrosis factor-alpha, interferon-gamma, interleukin-2, -4, -5, or -10, in a peripheral-blood mononuclear cell-culture medi uM were measured with beads-array procedures. The median (range) IC50 value for betamethasone butyratepropionate evaluated in the streptococcal pyrogenic enterotoxin A-stimulated peripheral-blood mononuclear cells was 291.6 (0.001-1171.5) ng/mL, which was significantly higher than the value 0.072 (0.01-222.5) ng/mL found in concanavalin A-stimulated peripheral-blood mononuclear cells (P=0.0245). However, the median (range) IC50 value for calcipotriol in the streptococcal pyrogenic enterotoxin A-stimulated peripheral-blood mononuclear cells was 0.3 (0.24-1357.4) ng/mL, which was significantly lower than the value 128.6 (0.1-776.9) ng/mL found in concanavalin A-stimulated peripheral-blood mononuclear cells (P=0.0323). The IC50 value for cyclosporine was not significantly different between the concanavalin A- and streptococcal pyrogenic enterotoxin A-stimulated PBMCs. Concentration for none of the cytokines was significantly different between concanavalin A- and streptococcal pyrogenic enterotoxin A-stimulated peripheral-blood mononuclear cell cultures. The effects of betamethasone butyrate propionate to suppress these cytokine productions were rather stronger than those of calcipotriol. Streptococcal pyrogenic enterotoxin A induced by hemolytic streptococci colonization is suggestedto attenuate the therapeutic efficacy of betamethasone butyrate propionate. While the mechanistic background of calcipotriol to suppress streptococcal pyrogenic enterotoxin A-induced peripheral-bloodmononuclear cell-proliferation remains to be elucidated, vitamin D3 derivatives appears to be effective in suppressing anomalistic immunity in patients having hemolytic streptococci colonization.	[2]
References
REF 1	Low-calcemic, highly antiproliferative, 1-difluoromethyl hybrid analogs of the natural hormone 1alpha,25-dihydroxyvitamin D3: design, synthesis, an... J Med Chem. 2006 Dec 14;49(25):7513-7.
REF 2	Comparative study of the effects of betamethasone butyrate propionate, vitamin D3 derivatives, and cyclosporine on human lymphocyte-proliferation s... Eur J Pharmacol. 2007 Oct 1;571(2-3):222-30.
REF 3	Antiproliferative effect of vitamin A and D analogues on adult human keratinocytes in vitro. Skin Pharmacol Physiol. 2008;21(4):227-34.
REF 4	Chondro/osteoblastic and cardiovascular gene modulation in human artery smooth muscle cells that calcify in the presence of phosphate and calcitriol or paricalcitol. J Cell Biochem. 2010 Nov 1;111(4):911-21.

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