Journal Article

Design of selective nuclear receptor modulators: RAR and RXR as a case study

Bourguet, William, de Lera, Angel R., Altucci, Lucia, Gronemeyer, Hinrich

2007

Overview

Key Points Small-molecule ligands that modulate the action of retinoic acid receptors (RARs) and retinoid X receptors (RXRs) — members of the nuclear receptor superfamily — have been used as anticancer drugs. However, their use can be limited by side effects. RARs and RXRs are each expressed from three isotypic genes (α,β and γ). The receptors are composed of a modular structure with several domains and associated functions. The main domains are the DNA-binding domain (DBD) and the ligand-binding domain (LBD). Drug discovery efforts are focusing on isotype-selective modulators to reduce toxicity associated with current retinoid therapy; elicit more specific biological responses, because the tissue distribution of retinoid receptor isotypes is not uniform; better define the physiological role of each retinoid receptor isotype; and clarify the potential of RXR-targeted pharmacology. Various crystal structures of RARs and RXRs have been elucidated, allowing for the correlation of ligand structure and (allosterically altered) receptor structure with the functional properties of the ligand-bound receptor. This information will provide guidelines for the design of novel analogues, and advances in synthetic organic chemistry will also be useful in the development of isotype-selective ligands with a range of activities from agonists to inverse agonists through to powerful antagonists. Retinoic acid receptors (RARs) are important drug targets for cancer therapy and prevention, and the potential of rexinoids for the treatment of metabolic diseases is increasingly being recognized. This article reviews recent structural data for RARs and retinoid X receptors (RXRs), discusses 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. 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: Animals / Biochemistry, Molecular Biology / Biomedical and Life Sciences / Biomedicine / Biotechnology / Cancer Research / Drug Design / Humans / Life Sciences / Ligands / Ligands (Biochemistry) / Medicinal Chemistry / Models, Molecular / Molecular biology / Molecular Medicine / Molecular Structure / Pharmacology/Toxicology / Physiological aspects / Protein Binding / Receptors, Retinoic Acid / Receptors, Retinoic Acid - agonists / Receptors, Retinoic Acid - antagonists & inhibitors / Receptors, Retinoic Acid - chemistry / Retinoid X Receptors / Retinoid X Receptors - agonists / Retinoid X Receptors - antagonists & inhibitors / Retinoid X Receptors - chemistry / Retinoids / Retinoids - chemical synthesis / Retinoids - chemistry / Retinoids - pharmacology / review-article / Tretinoin