5lwp

Discovery of phenoxyindazoles and phenylthioindazoles as RORg inverse agonists

spinqualitylabelsall models 5lwp, resolution 2.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5lwp is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 79U Gene: RORC, NR1F3, RORG, RZRG (HUMAN) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [RORG_HUMAN] Possible nuclear receptor for hydroxycholesterols, the binding of which strongly promotes coactivators recruitment. Essential for thymopoiesis and the development of several secondary lymphoid tissues, including lymph nodes. Involved in lineage specification of uncommitted CD4(+) T-helper cells into Th17 cells. Regulate the expression of several components of the circadian clock. Publication Abstract from PubMed Targeting the IL17 pathway and more specifically the nuclear receptor RORgamma is thought to be beneficial in multiple skin disorders. The Letter describes the discovery of phenoxyindazoles and thiophenoxy indazoles as potent RORgamma inverse agonists. Optimization of the potency and efforts to mitigate the phototoxic liability of the series are presented. Finally, crystallization of the lead compound revealed that the series bound to an allosteric site of the nuclear receptor. Such compounds could be useful as tool compounds for understanding the impact of topical treatment on skin disease models. Discovery of phenoxyindazoles and phenylthioindazoles as RORgamma inverse agonists.,Ouvry G, Bouix-Peter C, Ciesielski F, Chantalat L, Christin O, Comino C, Duvert D, Feret C, Harris CS, Lamy L, Luzy AP, Musicki B, Orfila D, Pascau J, Parnet V, Perrin A, Pierre R, Polge G, Raffin C, Rival Y, Taquet N, Thoreau E, Hennequin LF Bioorg Med Chem Lett. 2016 Dec 1;26(23):5802-5808. doi:, 10.1016/j.bmcl.2016.10.023. Epub 2016 Oct 12. PMID:27815118 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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