6sbo | pdb_00006sbo

Estrogen receptor mutant L536S

spinqualitylabelsall models 6sbo, resolution 1.48Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6sbo is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: L5B Gene: ESR1, ESR, NR3A1 (HUMAN) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [ESR1_HUMAN] Nuclear hormone receptor. The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Ligand-dependent nuclear transactivation involves either direct homodimer binding to a palindromic estrogen response element (ERE) sequence or association with other DNA-binding transcription factors, such as AP-1/c-Jun, c-Fos, ATF-2, Sp1 and Sp3, to mediate ERE-independent signaling. Ligand binding induces a conformational change allowing subsequent or combinatorial association with multiprotein coactivator complexes through LXXLL motifs of their respective components. Mutual transrepression occurs between the estrogen receptor (ER) and NF-kappa-B in a cell-type specific manner. Decreases NF-kappa-B DNA-binding activity and inhibits NF-kappa-B-mediated transcription from the IL6 promoter and displace RELA/p65 and associated coregulators from the promoter. Recruited to the NF-kappa-B response element of the CCL2 and IL8 promoters and can displace CREBBP. Present with NF-kappa-B components RELA/p65 and NFKB1/p50 on ERE sequences. Can also act synergistically with NF-kappa-B to activate transcription involving respective recruitment adjacent response elements; the function involves CREBBP. Can activate the transcriptional activity of TFF1. Also mediates membrane-initiated estrogen signaling involving various kinase cascades. Isoform 3 is involved in activation of NOS3 and endothelial nitric oxide production. Isoforms lacking one or several functional domains are thought to modulate transcriptional activity by competitive ligand or DNA binding and/or heterodimerization with the full length receptor. Isoform 3 can bind to ERE and inhibit isoform 1. Publication Abstract from PubMed More than 75 % of breast cancers are estrogen receptor alpha (ER) positive (ER+) and resistance to current hormone therapies occurs in one third of ER+ patients. Tumor resistance is still ERdependent, but mutations usually confer constitutive activation to the hormone-receptor, rendering ERmodulator drugs such as tamoxifen and aromatase inhibitors ineffective. Fulvestrant is a potent Selective Estrogen Receptor Degrader (SERD), which degrades the ERreceptor in drug-resistant tumors and has been approved for the treatment of hormone receptor positive metastatic breast cancer following antiestrogen therapy. However, fulvestrant shows poor pharmacokinetic properties in human, low solubility, weak permeation and high metabolism, limiting its administration to inconvenient intramuscular injections. This paper describes the identification and optimization of a new series of potent orally available SERDs, which led to the discovery of 6-(2,4-Dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8, 9-dihydro-7H-benzo[7]annulene-2-carboxylic acid (43d), showing promising antitumor activity in breast cancer mice xenograft models and whose properties warranted clinical evaluation. Discovery of 6-(2,4-Dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8, 9-dihydro-7H-benzo[7]annulene-2-carboxylic acid (SAR439859), a Potent and Selective Estrogen Receptor Degrader (SERD) for the Treatment of Estrogen Receptor Positive Breast Cancer.,Elahmad Y, Tabart M, Halley F, Certal V, Thompson F, Filoche-Romme B, Gruss-Leleu F, Muller C, Brollo M, Fabien L, Loyau V, Bertin L, Richepin P, Pilorge F, Desmazeau P, Girardet C, Beccari S, Louboutin A, Lebourg G, Le-Roux J, Terrier C, Vallee F, Steier V, Mathieu M, Rak A, Abecassis PY, Vicat P, Benard T, Bouaboula M, Sun F, Shomali M, Hebert A, Levit M, Cheng H, Courjaud A, Ginesty C, Perrault C, Garcia-Echeverria C, McCort G, Schio L J Med Chem. 2019 Nov 13. doi: 10.1021/acs.jmedchem.9b01293. PMID:31721572 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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