Retinoic acid receptor modulators: a perspective on recent advances and promises

Retinoids are currently used in the clinic for the treatment of skin diseases and acute promielocytic leukemia and are known to contribute to early development and organogenesis in embryo and throughout life. Most of these activities are primarily due to the binding of the retinoid to the retinoic acid receptors (RARs, subtypes α, β and γ). Ligand modulates, via allosteric conformational changes, the ability of RARs to interact with different sets of co-regulators. Structure-based insights on the ligand-binding domain of the ligand-bound RARs have clearly linked retinoid function to co-activator (CoA) recruitment for agonists, CoA dissociation for antagonists and corepressor stabilization for inverse agonists.

To help understand ligand-modulated RAR action as a consequence of its interaction with different sets of co-regulators, we present the chemical engineering of subsets of retinoid chemotypes (rexinoids, i.e., the ligands of the retinoid X receptors, α, β and γ, with impact in the treatment of cancer and metabolic diseases, are not covered) that display the whole range of ligand functions, including subtype- and isotype-selectivities.

An understanding of the correlation of retinoid ligand structure and function. Structural insights into ligand action and retinoid chemotypes. Potential for clinical application of retinoid receptor modulators.

Potential pharmacological/therapeutic applications of these chemical tools extend beyond cancer prevention and therapy to the treatment of autoimmune and neurodegenerative diseases.