Evaluation of vitamin D3 A-ring analogues as Hedgehog pathway inhibitors.
A structure-activity relationship study focusing on the A-ring of vitamin D3 (VD3) was undertaken to elucidate its role in inhibiting the Hedgehog pathway and in mediating anti-cancer effects. Analogues resulting from simple functional group substitution at 3' position of VD3 were evaluated in a variety of biological assays to determine their ability to selectively inhibit Hh signaling. Moderately active Hh inhibitors that have insignificant binding affinity for VDR were identified; however, these compounds also activate the traditional VDR pathway, presumably due to metabolites produced in the cultured cells. Thus, further structural modifications to the VD3 scaffold are required to yield potent, selective Hh inhibitors.
Department of Pharmaceutical Sciences, University of Connecticut, 69 N Eagleville Rd., Unit 3092, Storrs, CT 06269-3092, USA.
Upasana
U
Banerjee
Manuka
M
Ghosh
M
M
Kyle Hadden
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002762:Cholecalciferol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D015394:Molecular Structure; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D053823:Hedgehog Proteins; D002762:Cholecalciferol