Query String: GW4064
- Smalley, TL; Boggs, S; Caravella, JA; Chen, L; Creech, KL; Deaton, DN; Kaldor, I; Parks, DJ Novel heterocyclic scaffolds of GW4064 as farnesoid X receptor agonists. Bioorg Med Chem Lett 25: 280-4 (2014)
- Bass, JY; Caldwell, RD; Caravella, JA; Chen, L; Creech, KL; Deaton, DN; Madauss, KP; Marr, HB; McFadyen, RB; Miller, AB; Parks, DJ; Todd, D; Williams, SP; Wisely, GB Substituted isoxazole analogs of farnesoid X receptor (FXR) agonist GW4064. Bioorg Med Chem Lett 19: 2969-73 (2009)
- Feng, S; Yang, M; Zhang, Z; Wang, Z; Hong, D; Richter, H; Benson, GM; Bleicher, K; Grether, U; Martin, RE; Plancher, JM; Kuhn, B; Rudolph, MG; Chen, L Identification of an N-oxide pyridine GW4064 analog as a potent FXR agonist. Bioorg Med Chem Lett 19: 2595-8 (2009)
- Flesch, D; Gabler, M; Lill, A; Gomez, RC; Steri, R; Schneider, G; Stark, H; Schubert-Zsilavecz, M; Merk, D Fragmentation of GW4064 led to a highly potent partial farnesoid X receptor agonist with improved drug-like properties. Bioorg Med Chem 23: 3490-8 (2015)
- Misawa, T; Hayashi, H; Makishima, M; Sugiyama, Y; Hashimoto, Y E297G mutated bile salt export pump (BSEP) function enhancers derived from GW4064: structural development study and separation from farnesoid X receptor-agonistic activity. Bioorg Med Chem Lett 22: 3962-6 (2012)
- ChEMBL_2298045 Antagonist activity at FXR-LBD-GST (unknown origin) in presence of GW4064
- ChEMBL_1348162 (CHEMBL3269921) Inhibition of GW4064-induced transactivation of FXR (unknown origin) expressed in HEK293T cells after 16 hrs by beta-lactamase reporter gene assay
- ChEMBL_1645080 (CHEMBL3994009) Inhibition of GW4064-induced fluorecein-labeled SRC2-2 coactivator recruitment in GST-tagged FXR LBD (unknown origin) by Lanthascreen TR-FRET assay
- ChEMBL_1581916 (CHEMBL3816769) Antagonist activity at human FXR expressed in HEK293 cells assessed as inhibition of GW4064-induced transactivation after 24 hrs by luciferase reporter gene assay
- ChEBML_1729515 Antagonist activity at GST-tagged FXR LBD (unknown origin) assessed as inhibition of GW4064-induced fluorecein-labeled SRC2-2 coactivator recruitment by Lanthascreen TR-FRET assay
- ChEMBL_1729515 (CHEMBL4144793) Antagonist activity at GST-tagged FXR LBD (unknown origin) assessed as inhibition of GW4064-induced fluorecein-labeled SRC2-2 coactivator recruitment by Lanthascreen TR-FRET assay
- ChEMBL_1841526 (CHEMBL4341825) Antagonist activity at GST-tagged FXR LBD (unknown origin) assessed as inhibition of GW4064-induced fluorecein-labeled SRC2-2 coactivator recruitment by Lanthascreen TR-FRET assay
- ChEMBL_2035579 (CHEMBL4689737) Antagonist activity at recombinant GST-tagged FXR LBD (unknown origin) assessed as inhibition of GW4064-induced Fluorecein-SRC2-2 coactivator peptide recruitment by LanthaScreen TR-FRET co-regulator assay
- ChEMBL_2186889 (CHEMBL5098971) Antagonist activity at FXR (unknown origin) expressed in HEK293T cells cotransfected with pCMV-Script-hFXR/pGL4.11-hSHP-Luciferase incubated for 24 hrs in presence of GW4064 by Steady-glo luciferase assay
- ChEMBL_1777020 (CHEMBL4234012) Antagonist activity at full length human FXR expressed in HeLa cells co-expressing BSEP-pGL3/pSG5-hRXR assessed as inhibition of GW4064-induced receptor activation after 24 hrs by luciferase reporter gene assay
- ChEMBL_2069832 (CHEMBL4725085) Antagonist activity at human FXR-LBD transfected in human HEK293T cells co-expressing pFR-Luc/pRL assessed as reduction in GW4064-induced activity incubated for 14 to 16 hrs by hybrid reporter gene assay
- Scintillation Proximity Assay (IC50) and Cell-Based Transactivation Assay (EC50) Binding affinity (IC50) was evaluated using scintillation proximity assay with radiolabeled ligand and biotinylated receptor. Because the scintillant is contained within the SPA bead, only radiolabel that is attached to the bead is detected. The receptor-ligand complex is bound to the bead through interaction between the biotinylated receptor and the streptavidin moiety located on the surface of the bead. EC50 was measured by luciferase transcriptional reporter gene assays. Efficacies are relative to GW4064.
- FXR Ligand Binding Assay The affinity of FXR ligands for the ligand binding domain of FXR was determined using a commercially available human FXR ligand binding assay (LanthaScreen, Thermofisher Cat #PV4833). The purified ligand binding domain of human FXR tagged with GST (glutathiones-S-transferase) is incubated with a terbium labelled anti-GLT antibody and a fluorescein-labelled SRC2-2 peptide (LKEKHKILHRLLQDSSSPV (SEQ ID No.: 1)). Binding of FXR ligands to the FXR ligand binding domain promotes binding of the fluorescein-labelled SRC2-2 peptide. This causes a FRET signal between the terbium-labelled anti-GST antibody and the fluorescein-labelled SRC peptide which are both bound to the FXR ligand binding domain. Test compounds are dissolved in DMSO and a 3-fold serial dilution series is generated, then further diluted into assay buffer. The compounds are mixed with 5 nM GST-tagged FXR ligand binding domain, 5 nM Tb-labelled anti-GST antibody and 500 nM fluorescein-labelled SRC2-2 peptide in a pH 7.4 buffer. The reaction is incubated at room temperature for 1 hour, then the FRET signal is measured as the ratio of the 520 nm/495 nm emission following excitation at 340 nm. The change in FRET signal is plotted against the test article concentration and fit to a 3-parameter logistical equation. The concentration required to produce 50% activation is expressed as pEC50 (−log EC50), and the extent of activation is expressed relative to GW4064 as % activation.