Probing the structural requirements for vitamin D3 inhibition of the hedgehog signaling pathway.
A structure-activity relationship study to elucidate the structural basis for hedgehog (Hh) signaling inhibition by vitamin D3 (VD3) was performed. Functional and non-functional regions of VD3 and VD2 were obtained through straightforward synthetic means and their biological activity was determined in a variety of cell-based assays. Several of these compounds inhibited Hh signaling at levels comparable to the parent VD3 with no effects on canonical vitamin D signaling. Most notably, compounds 5 and 9, demonstrated potent inhibition of the Hh pathway, exhibited no binding affinity for the vitamin D receptor (VDR), and did not activate VDR in cell culture. In addition, several compounds exhibited anti-proliferative activity against two human cancer cell lines through a mechanism distinct from the Hh or VDR pathways, suggesting a new cellular mechanism of action for this class of compounds.
Department of Pharmaceutical Sciences, University of Connecticut, 69 N Eagleville Rd., Unit 3092, Storrs, CT 06269-3092, USA.
Albert M
AM
DeBerardinis
Upasana
U
Banerjee
Michele
M
Miller
Steven
S
Lemieux
M Kyle
MK
Hadden
D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002762:Cholecalciferol / Q000037:antagonists & inhibitors*; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D015394:Molecular Structure; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship
D053823:Hedgehog Proteins; D002762:Cholecalciferol