Target Validation Information
TTD ID	TTDS00251
Target Name	Vitamin D receptor
Type of Target	Successful target
Drug Potency against Target	Paricalcitol		EC50 = 8.7 nM	[1]
	Calcitriol		IC50 = 0.6 nM	[2]
	Calcipotriol		IC50 = 1.8 nM	[2]
	Ergocalciferol		IC50 = 1910 nM	[3]
	KSP-BCS-1-alpha-CHF2-20-epi-22-oxabishomo-26-OH		IC50 = 19.5 nM	[4]
	KSP-BCS-1-alpha-CHF2-1624F2-2		IC50 = 50 nM	[4]
Action against Disease Model	Calcipotriol		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 butyrate propionate 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 suggested to attenuate the therapeutic efficacy of betamethasone butyrate propionate. While the mechanistic background of calcipotriol to suppress streptococcal pyrogenic enterotoxin A-induced peripheral-blood mononuclear cell-proliferation remains to be elucidated, vitamin D3 derivatives appears to be effective in suppressing anomalistic immunity in patients having hemolytic streptococci colonization.	[5]
Ref 1	J Cell Biochem. 2010 Nov 1;111(4):911-21.Chondro/osteoblastic and cardiovascular gene modulation in human artery smooth muscle cells that calcify in the presence of phosphate and calcitriol or paricalcitol. To Reference
Ref 2	Fluorescence-based methods for the characterization of vitamin D receptor ligands To Reference
Ref 3	Skin Pharmacol Physiol. 2008;21(4):227-34. Epub 2008 May 29.Antiproliferative effect of vitamin A and D analogues on adult human keratinocytes in vitro. To Reference
Ref 4	J Med Chem. 2006 Dec 14;49(25):7513-7.Low-calcemic, highly antiproliferative, 1-difluoromethyl hybrid analogs of the natural hormone 1alpha,25-dihydroxyvitamin D3: design, synthesis, and preliminary biological evaluation. To Reference
Ref 5	Eur J Pharmacol. 2007 Oct 1;571(2-3):222-30. Epub 2007 Jun 29.Comparative study of the effects of betamethasone butyrate propionate, vitamin D3 derivatives, and cyclosporine on human lymphocyte-proliferation stimulated with a hemolytic streptococci-derived superantigen. To Reference

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Dr. Chen Yuzong
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Professor in Department of Pharmacy
National University of Singapore, Singapore

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