Synthetic Retinoids and Their Nuclear Receptors

Abstract

In addition to all-trans-retinoic acid and its 9 and 13-cis isomers, four synthetic retinoids are currently available to treat diseases of hyperproliferation, such as acne, psoriasis, and actinic keratosis, or cancers such as acute promelocytic leukemia, cutaneous T-cell lymphoma, and squamous or basal cell carcinoma. The retinoids extert their antiproliferative effects by interacting with their retinoic acid and retinoid X receptors that act as ligand-inducible transcription factors. These homologous receptors function either directly on retinoid response elements or indirectly by modifying the responses of other transcription factors. Their major domains for binding DNA and their ligands have been characterized by either nuclear magnetic resonance spectroscopy or X-ray crystallography. The identification and design of synthetic retinoids are overviewed, as are their selective interactions with specific retinoid receptor subtypes and their clinical effects against cancer. Emphasis is placed on the retinoid X receptors and their ligands.

International Union of Pharmacology. LXIII. Retinoid X Receptors

“…Initially, 9CRA was identified as an agonist for RXRs, but it is not an RXR-selective compound because it displays a high affinity for all three RARs Dawson, 2004). The most widely use rexinoids are SR11237, LG100268, and LGD1069, which is currently used in therapy (see below) .…”

Model examinatio�n of chemoprevention with retinoids in squamous cell carcinomas of the head and neck region and suitable biomarkers for chemoprevention

“…Since the effects of retinoids are mediated via their nuclear RAR and RXR receptors (66)(67)(68)(69)(70)(71)(72)(73), ATRA more effectively by the three RAR receptors (RARα, RARβ and RARγ), we examined RAR (RARα and RARβ) and RXR receptors (RXRγ) on the three cell lines (Fig. 2).…”

“…The activation and the affinity of the receptors are dependent on the particular retinoids being used: ATRA prefers a ligand for RAR receptors while 9-cis-RA prefers RXRs receptors but will also bind RAR receptors (66)(67)(68)(69)(70)(71)(72)(73). The selectivity of the retinoids and rexinoids to particular receptors is probably also the explanation for their differing therapeutic effects.…”

“…The selectivity of the retinoids and rexinoids to particular receptors is probably also the explanation for their differing therapeutic effects. The discovery of the RA receptors in 1987 (66)(67)(68)(69)(74)(75)(76) was followed shortly by the development of synthetic retinoids, above all of synthetic receptor-selective retinoids (70,71). In retinoic therapy, the growth and differentiation of cancer cells is modulated, presumably through the activation of gene transcription by nuclear RA receptors RAR and RXR (61).…”

Potential of retinoic acid derivatives for the treatment of corticotroph pituitary adenomas

“…The search for isotype-selective modulators [15,[34][35][36]] is pursued to first, reduce side effects associated with current retinoid therapy; second, elicit more specific biological responses, because the tissue distribution of retinoid receptors isotypes is not uniform, third, better define the physiological role of each retinoid receptor isotype in the control of certain biological phenomena such as proliferation, differentiation and apoptosis [15].…”