4zjr | pdb_00004zjr
RORgamma in complex with inverse agonist 48
Structural highlights
FunctionRORG_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 PubMedRORgammat is a pivotal regulator of a pro-inflammatory gene expression program implicated in the pathology of several major human immune-mediated diseases. Evidence from mouse models demonstrates that genetic or pharmacological inhibition of RORgamma activity can block the production of pathogenic cytokines, including IL-17, and convey therapeutic benefit. We have identified and developed a biaryl-carboxylamide series of RORgamma inverse agonists via a structure based design approach. Co-crystal structures of compounds 16 and 48 supported the design approach and confirmed the key interactions with RORgamma protein; the hydrogen bonding with His479 was key to the significant improvement in inverse agonist effect. The results have shown this is a class of potent and selective RORgamma inverse agonists, with demonstrated oral bioavailability in rodents. Discovery of biaryl carboxylamides as potent RORgamma inverse agonists.,Chao J, Enyedy I, Van Vloten K, Marcotte D, Guertin K, Hutchings R, Powell N, Jones H, Bohnert T, Peng CC, Silvian L, Hong VS, Little K, Banerjee D, Peng L, Taveras A, Viney JL, Fontenot J Bioorg Med Chem Lett. 2015 Aug 1;25(15):2991-7. doi: 10.1016/j.bmcl.2015.05.026. , Epub 2015 May 23. PMID:26048806[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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