Molecular evaluation of vitamin D3 receptor agonists designed for topical treatment of skin diseases

MC903 (calcipotriol) is a synthetic, low calcemic analog of the nuclear hormone 1 alpha ,25-dihydroxyvitamin D-3 and used in the treatment of psoriasis. The beneficial effects of MC903 on psoriasis are based on gene regulatory events. The genomic actions of 1 alpha ,25-dihydroxyvitamin D-3 and its analogs are primarily mediated by a complex of the vitamin D-3 receptor and the retinoid X receptor bound to a 1 alpha ,25-dihydroxyvitamin D-3 response element that can be considered as the molecular switch of 1 alpha ,25-dihydroxyvitamin D-3 signaling. In this study, the interaction of MC903 and two new analogs, GS1500 and EB1213, with this molecular switch was compared with that of 1 alpha ,25-dihydroxyvitamin D-3. In DNA-dependent limited protease digestion assays, ligand-dependent gel shift assays and mammalian-one-hybrid assays, all four ligands appeared to be equally sensitive VDR agonists that activated vitamin D-3 receptor-retinoid X receptor-1 alpha ,25-dihydroxyvitamin D-3 response element complexes at a concentration of approximately 0.2 nM. The analyzed VDR agonists, however, also showed individual molecular properties, such as a reduced sensitivity in HaCaT cells (MC903), a selectivity for DNA-bound vitamin D-3 receptor-retinoid X receptor heterodimers (GS1500) and a long-lasting stabilization of vitamin D-3 receptor-retinoid X receptor-1 alpha ,25-dihydroxyvitamin D-3 response element complexes (EB1213). This molecular evaluation demonstrated that the sensitivity in activating the vitamin D3 receptor is already optimal for MC903, but the analog may not be ideal in keeping the receptor active and in selectively triggering 1 alpha ,25-dihydroxyvitamin D-3 signaling pathways.