Retinoic Acid Receptor Related Drug Discovery Products

The retinoic acid receptor (RAR) assemblage, a constituent subset of the nuclear receptor superfamilial aggregation, assumes an essential function in a plethora of physiological phenomena, encompassing cellular differentiation, proliferation, and homeostatic maintenance. RARs chiefly operate as ligand-induced transcriptional modulators, adhering to retinoic acid (RA) and orchestrating the expression patterns of pertinent genetic targets. The intricacy of RA signaling, amalgamated with its conceivable involvement in diverse pathological circumstances, has designated RARs as propitious candidates for pharmacological exploration.

Fig.1 RA activates RAR and PPARβ/δ. (Michalik, 2007)

Creative Biolabs we can offer retinoic acid receptor drug discovery tools to help scientists accelerate drug discovery and development projects:

• Retinoic Acid Receptor Assays
• Membrane Protein Tools

Overview of Retinoic Acid Receptors

The RAR family comprises three main subtypes, namely RARα, RARβ, and RARγ, each encoded by distinct genes. These receptors share a highly conserved structure, with a central DNA-binding domain (DBD) and a C-terminal ligand-binding domain (LBD). Upon RA binding, RARs typically form heterodimers with retinoid X receptors (RXRs), which subsequently bind to specific DNA sequences known as retinoic acid response elements (RAREs) in the promoter regions of target genes. This binding event modulates the transcriptional activity of target genes, thereby eliciting a multitude of downstream effects on cellular processes.

Mechanisms of Retinoic Acid Receptor Action

The adherence of RA to the ligand-binding domain (LBD) of RARs provokes a conformational metamorphosis, fostering the enlistment of coactivator proteins and the liberation of corepressor constituents. This fluid interaction between coactivators and corepressors delineates the transcriptional vigor of RAR-associated genetic targets. It is noteworthy that the particularity of RA signaling is bestowed by the disparate expression patterns and propensities of RAR subcategories for diverse RA isoforms, in conjunction with the existence of cell type-specific coregulatory elements.

Fig.2 Mechanisms of RA signaling. (Conserva, 2019)

Retinoic Acid Receptor Drug Discovery

The multifaceted roles of RARs in various physiological processes have sparked considerable interest in their potential as therapeutic targets for a diverse array of diseases. Some of the key areas of focus in drug discovery involving RARs include:

Dermatological Disorders: RARs play a crucial role in skin homeostasis and differentiation, which has driven the development of RAR-targeting therapies for various skin conditions. By modulating keratinocyte proliferation and differentiation, as well as inflammation, these therapies may hold promise for managing a wide range of dermatological disorders.

Oncology: Dysregulation of RAR signaling has been implicated in the pathogenesis of several malignancies, including certain hematological and solid tumors. RAR-targeting therapies have demonstrated efficacy in inducing terminal differentiation of cancerous cells, and further research is needed to explore the potential roles of RARs in other cancer types and to develop novel therapies with improved selectivity and efficacy.

Neurological Disorders: Emerging evidence suggests that RARs may play significant roles in neurogenesis, synaptic plasticity, and neuronal survival. As a result, RAR-targeting therapies may have potential for the treatment of various neurological disorders by modulating neuroinflammation, neuronal differentiation, and synaptic function.

References

1. Michalik, L.; Wahli, W. Guiding ligands to nuclear receptors. Cell. 2007, 129(4): 649-651.
2. Conserva, M.R.; et al. The pleiotropic role of retinoic acid/retinoic acid receptors signaling: from vitamin A metabolism to gene rearrangements in Acute Promyelocytic Leukemia. International Journal of Molecular Sciences. 2019, 20(12): 2921.