Identification of novel subtype selective RAR agonists.
Drugs targeting retinoid receptors have been developed to treat a variety of therapeutic indications, but their success has been limited in part due to lack of selectivity. A novel functional cell-based assay R-SATtrade mark was employed to screen a small molecule chemical library and identify a variety of novel RAR agonists with various subtype selectivities, including RARbeta/gamma and RARgamma selective agonists. A novel class of synthetic compounds that distinguishes between the different RARbeta isoforms is described. This pharmacophore displays anti-proliferative activity and induces differentiation in a neuronal cell line, consistent with a classical retinoid mechanism of action while providing unique subtype selectivity. These novel subtype selective RAR agonists could serve as powerful tools to probe into subtype and isoform-specific retinoid function.
Piu
Fabrice
F
ACADIA Pharmaceuticals Inc., San Diego, CA 92131, USA. fpiu@acadia-pharm.com
Gauthier
Natalie K
NK
Olsson
Roger
R
Currier
Erika A
EA
Lund
Birgitte W
BW
Croston
Glenn E
GE
Hacksell
Uli
U
Brann
Mark R
MR
D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D006801:Humans; D051379:Mice; D016501:Neurites; D018168:Receptors, Retinoic Acid / Q000819:agonists*
D018168:Receptors, Retinoic Acid