Molecular Interactions of Selective Agonists and Antagonists with the Retinoic Acid Receptor γ

• Published in: International journal of molecular sciences Vol. 25; no. 12; p. 6568
• Main Authors: Powała, Katarzyna, Żołek, Teresa, Brown, Geoffrey, Kutner, Andrzej
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.06.2024; MDPI
• Subjects: AGN205728; Alitretinoin; Amino acids; Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; ATRA; Cancer; cancer stem cells; Cell differentiation; Drug development; Gene expression; Genes; Humans; Leukemia; Leukemia, Promyelocytic, Acute - drug therapy; Leukemia, Promyelocytic, Acute - metabolism; Ligands; Oncology, Experimental; Protein Binding; RARγ antagonists; receptor RARγ; Receptors, Retinoic Acid - agonists; Receptors, Retinoic Acid - metabolism; Retinoic Acid Receptor gamma; retinoids; Review; RNA polymerase; Stem cells; Transcription factors; Tretinoin - pharmacology; Vitamin A; RARγ antagonists; cancer stem cells; ATRA; receptor RARγ; retinoids; AGN205728
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms25126568

All- retinoic acid (ATRA), the major active metabolite of all- retinol (vitamin A), is a key hormonal signaling molecule. In the adult organism, ATRA has a widespread influence on processes that are crucial to the growth and differentiation of cells and, in turn, the acquisition of mature cell functions. Therefore, there is considerable potential in the use of retinoids to treat diseases. ATRA binds to the retinoic acid receptors (RAR) which, as activated by ATRA, selectively regulate gene expression. There are three main RAR isoforms, RARα, RARβ, and RARγ. They each have a distinct role, for example, RARα and RARγ regulate myeloid progenitor cell differentiation and hematopoietic stem cell maintenance, respectively. Hence, targeting an isoform is crucial to developing retinoid-based therapeutics. In principle, this is exemplified when ATRA is used to treat acute promyelocytic leukemia (PML) and target RARα within PML-RARα oncogenic fusion protein. ATRA with arsenic trioxide has provided a cure for the once highly fatal leukemia. Recent in vitro and in vivo studies of RARγ have revealed the potential use of agonists and antagonists to treat diseases as diverse as cancer, heterotopic ossification, psoriasis, and acne. During the final drug development there may be a need to design newer compounds with added modifications to improve solubility, pharmacokinetics, or potency. At the same time, it is important to retain isotype specificity and activity. Examination of the molecular interactions between RARγ agonists and the ligand binding domain of RARγ has revealed aspects to ligand binding that are crucial to RARγ selectivity and compound activity and key to designing newer compounds.