Design of selective nuclear receptor modulators: RAR and RXR as a case study.
Retinoic acid receptors (RARs) and retinoid X receptors (RXRs) are members of the nuclear receptor superfamily whose effects on cell growth and survival can be modulated therapeutically by small-molecule ligands. Although compounds that target these receptors are powerful anticancer drugs, their use is limited by toxicity. An improved understanding of the structural biology of RXRs and RARs and recent advances in the chemical synthesis of modified retinoid and rexinoid ligands should enable the rational design of more selective agents that might overcome such problems. Here, we review structural data for RXRs and RARs, discuss strategies in the design of selective RXR and RAR modulators, and consider lessons that can be learned for the design of selective nuclear-receptor modulators in general.
de Lera
Angel R
AR
Universidade de Vigo, Departamento de Quimica Orgánica, Facultad de Quimica, 36310 Vigo, Spain.
Bourguet
William
W
Altucci
Lucia
L
Gronemeyer
Hinrich
H
D000818:Animals; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D018168:Receptors, Retinoic Acid / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry; D047488:Retinoid X Receptors / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry; D012176:Retinoids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D008024:Ligands; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D012176:Retinoids