6hty
From Proteopedia
PXR in complex with P2X4 inhibitor compound 25
Structural highlights
DiseaseNCOA1_HUMAN Note=A chromosomal aberration involving NCOA1 is a cause of rhabdomyosarcoma. Translocation t(2;2)(q35;p23) with PAX3 generates the NCOA1-PAX3 oncogene consisting of the N-terminus part of PAX3 and the C-terminus part of NCOA1. The fusion protein acts as a transcriptional activator. Rhabdomyosarcoma is the most common soft tissue carcinoma in childhood, representing 5-8% of all malignancies in children. FunctionNCOA1_HUMAN Nuclear receptor coactivator that directly binds nuclear receptors and stimulates the transcriptional activities in a hormone-dependent fashion. Involved in the coactivation of different nuclear receptors, such as for steroids (PGR, GR and ER), retinoids (RXRs), thyroid hormone (TRs) and prostanoids (PPARs). Also involved in coactivation mediated by STAT3, STAT5A, STAT5B and STAT6 transcription factors. Displays histone acetyltransferase activity toward H3 and H4; the relevance of such activity remains however unclear. Plays a central role in creating multisubunit coactivator complexes that act via remodeling of chromatin, and possibly acts by participating in both chromatin remodeling and recruitment of general transcription factors. Required with NCOA2 to control energy balance between white and brown adipose tissues. Required for mediating steroid hormone response. Isoform 2 has a higher thyroid hormone-dependent transactivation activity than isoform 1 and isoform 3.[1] [2] [3] [4] [5] [6] [7] NR1I2_HUMAN Nuclear receptor that binds and is activated by variety of endogenous and xenobiotic compounds. Transcription factor that activates the transcription of multiple genes involved in the metabolism and secretion of potentially harmful xenobiotics, drugs and endogenous compounds. Activated by the antibiotic rifampicin and various plant metabolites, such as hyperforin, guggulipid, colupulone, and isoflavones. Response to specific ligands is species-specific. Activated by naturally occurring steroids, such as pregnenolone and progesterone. Binds to a response element in the promoters of the CYP3A4 and ABCB1/MDR1 genes.[8] [9] [10] [11] [12] [13] Publication Abstract from PubMedThe P2X4 receptor is a ligand-gated ion channel that is expressed on a variety of cell types especially those involved in inflammatory and immune processes. High-throughput screening let to a new class of P2X4 inhibitors with substantial CYP 3A4 induction in human hepatocytes. A structure-guided optimization with respect to decreased PXR binding was started. It was found that the introduction of larger and more polar substituents on the ether linker led to less PXR binding while maintaining the P2X4 inhibitory potency. This translated into significantly reduced CYP-induction for compounds 71 and 73. Unfortunately, the in vivo PK profiles of these compounds were insufficient for the desired profile in humans. However, BAY-1797 (10) was identified and characterized as potent and selective P2X4 antagonist. This compound is suitable for in vivo studies in rodents, anti-inflammatory and anti-nociceptive effects of BAY-1797 were demonstrated in a mouse CFA inflammatory pain model. Discovery and Characterization of the Potent and Selective P2X4 Inhibitor N-[4-(3-Chlorophenoxy)-3-sulfamoylphenyl]-2-phenylacetamide (BAY-1797) and Structure- guided Amelioration of its CYP3A4 Induction Profile.,Werner S, Mesch S, Hillig RC, Ter Laak AM, Klint J, Neagoe I, Laux-Biehlmann A, Dahllof H, Braeuer N, Puetter V, Nubbemeyer R, Schulz S, Bairlein M, Zollner TM, Steinmeyer A J Med Chem. 2019 Nov 20. doi: 10.1021/acs.jmedchem.9b01304. PMID:31746599[14] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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Categories: Homo sapiens | Large Structures | Braeuer N | Dahloef H | Hillig RC | Klint J | Laux-Biehlmann A | Mesch S | Neagoe I | Nubbemeyer R | Pook E | Puetter V | Schulz S | Werner S | Ter Laak A
