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6fx0

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Structure-based design of Trifarotene (CD5789), a potent and selective RAR gamma agonist for the treatment of acne

Structural highlights

6fx0 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.9Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

RARG_HUMAN Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RAR/RXR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. In the absence of ligand, acts mainly as an activator of gene expression due to weak binding to corepressors. Required for limb bud development. In concert with RARA or RARB, required for skeletal growth, matrix homeostasis and growth plate function (By similarity).

Publication Abstract from PubMed

Retinoids have a dominant role in topical acne therapy and to date, only RARbeta and RARgamma dual agonists have reached the market. Given the tissue distribution of RAR isoforms, it was hypothesized that developing RARgamma -selective agonists could yield a new generation of topical acne treatments that would increase safety margins while maintaining the robust efficacy of previous drugs. Structural knowledge derived from the X-ray structure of known gamma-selective CD437, suggested the design of a novel triaryl series of agonists which was optimized and ultimately led to the discovery of Trifarotene/CD5789.

Structure-based design of Trifarotene (CD5789), a potent and selective RARgamma agonist for the treatment of acne.,Thoreau E, Arlabosse JM, Bouix-Peter C, Chambon S, Chantalat L, Daver S, Dumais L, Duvert G, Feret A, Ouvry G, Pascau J, Raffin C, Rodeville N, Soulet C, Tabet S, Talano S, Portal T Bioorg Med Chem Lett. 2018 Jun 1;28(10):1736-1741. doi:, 10.1016/j.bmcl.2018.04.036. Epub 2018 Apr 15. PMID:29706423^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Thoreau E, Arlabosse JM, Bouix-Peter C, Chambon S, Chantalat L, Daver S, Dumais L, Duvert G, Feret A, Ouvry G, Pascau J, Raffin C, Rodeville N, Soulet C, Tabet S, Talano S, Portal T. Structure-based design of Trifarotene (CD5789), a potent and selective RARgamma agonist for the treatment of acne. Bioorg Med Chem Lett. 2018 Jun 1;28(10):1736-1741. doi:, 10.1016/j.bmcl.2018.04.036. Epub 2018 Apr 15. PMID:29706423 doi:http://dx.doi.org/10.1016/j.bmcl.2018.04.036