AG 205 - CAS 442656-02-2
Catalog number: 442656-02-2
Category: Inhibitor
Please be kindly noted products are not for therapeutic use. We do not sell to patients.
Molecular Formula:
C22H23ClN6OS
Molecular Weight:
454.98
COA:
Inquire
Targets:
Progesterone Receptor
Description:
AG-205 is a novel Pgrmc1 (progesterone receptor membrane component 1) inhibitor, alters the spectroscopic properties of the Pgrmc1-heme complex.
Purity:
≥98%
Appearance:
Solid powder
Synonyms:
1-[(4aR,9bS)-2,8-dimethyl-3,4,4a,9b-tetrahydro-1H-pyrido[4,3-b]indol-5-yl]-2-[1-(4-chlorophenyl)tetrazol-5-yl]sulfanylethanone;
Solubility:
Soluble in DMSO
Storage:
Store at -20 °C
MSDS:
Inquire
Application:
PGRMC1-Inhibitor
Quality Standard:
Enterprise standard
Shelf Life:
As supplied, 2 years from the QC date provided on the Certificate of Analysis, when stored properly.
Quantity:
Milligrams-Grams
InChIKey:
GJNBAISSZRNGTM-UYAOXDASSA-N
InChI:
1S/C22H23ClN6OS/c1-14-3-8-19-17(11-14)18-12-27(2)10-9-20(18)28(19)21(30)13-31-22-24-25-26-29(22)16-6-4-15(23)5-7-16/h3-8,11,18,20H,9-10,12-13H2,1-2H3/t18-,20-/m1/s1
Canonical SMILES:
CC1=CC2=C(C=C1)N(C3C2CN(CC3)C)C(=O)CSC4=NN=NN4C5=CC=C(C=C5)Cl
1.Progesterone receptor membrane component 1 is a functional part of the glucagon-like peptide-1 (GLP-1) receptor complex in pancreatic β cells.
Zhang M;Robitaille M;Showalter AD;Huang X;Liu Y;Bhattacharjee A;Willard FS;Han J;Froese S;Wei L;Gaisano HY;Angers S;Sloop KW;Dai FF;Wheeler MB Mol Cell Proteomics. 2014 Nov;13(11):3049-62. doi: 10.1074/mcp.M114.040196. Epub 2014 Jul 20.
Glucagon-like peptide-1 (GLP-1) is an incretin hormone that regulates glucose homeostasis. Because of their direct stimulation of insulin secretion from pancreatic β cells, GLP-1 receptor (GLP-1R) agonists are now important therapeutic options for the treatment of type 2 diabetes. To better understand the mechanisms that control the insulinotropic actions of GLP-1, affinity purification and mass spectrometry (AP-MS) were employed to uncover potential proteins that functionally interact with the GLP-1R. AP-MS performed on Chinese hamster ovary cells or MIN6 β cells, both expressing the human GLP-1R, revealed 99 proteins potentially associated with the GLP-1R. Three novel GLP-1R interactors (PGRMC1, Rab5b, and Rab5c) were further validated through co-immunoprecipitation/immunoblotting, fluorescence resonance energy transfer, and immunofluorescence. Functional studies revealed that overexpression of PGRMC1, a novel cell surface receptor that associated with liganded GLP-1R, enhanced GLP-1-induced insulin secretion (GIIS) with the most robust effect. Knockdown of PGRMC1 in β cells decreased GIIS, indicative of positive interaction with GLP-1R. To gain insight mechanistically, we demonstrated that the cell surface PGRMC1 ligand P4-BSA increased GIIS, whereas its antagonist AG-205 decreased GIIS.
2.Identification of progesterone receptor membrane component-1 as an interaction partner and possible regulator of fatty acid 2-hydroxylase.
Hardt R;Winter D;Gieselmann V;Eckhardt M Biochem J. 2018 Mar 6;475(5):853-871. doi: 10.1042/BCJ20170963.
The fatty acid 2-hydroxylase (FA2H) is essential for synthesis of 2-hydroxylated fatty acids in myelinating and other cells, and deficiency of this enzyme causes a complicated form of hereditary spastic paraplegia also known as fatty acid hydroxylase-associated neurodegeneration. Despite its important role in sphingolipid metabolism, regulation of FA2H and its interaction with other proteins involved in the same or other metabolic pathways is poorly understood. To identify potential interaction partners of the enzyme, quantitative mass spectrometry using stable isotope labeling of cells was combined with formaldehyde cross-linking and proximity biotinylation, respectively. Besides other enzymes involved in sphingolipid synthesis and intermembrane transfer of ceramide, and putative redox partners of FA2H, progesterone receptor membrane component-1 (PGRMC1) and PGRMC2 were identified as putative interaction partners. These two related heme-binding proteins are known to regulate several cytochrome P450 enzymes. Bimolecular fluorescence complementation experiments confirmed the interaction of FA2H with PGRMC1. Moreover, the PGRMC1 inhibitor AG-205 significantly reduced synthesis of hydroxylated ceramide and glucosylceramide in FA2H-expressing cells.
3.AG 205, a progesterone receptor membrane component 1 antagonist, ablates progesterone's ability to block oxidative stress-induced apoptosis of human granulosa/luteal cells†.
Will EA;Liu X;Peluso JJ Biol Reprod. 2017 Apr 1;96(4):843-854. doi: 10.1093/biolre/iox013.
The present studies were designed to determine whether progesterone (P4)-progesterone receptor membrane component 1 (PGRMC1) signaling is able to attenuate the apoptotic effects of oxidative stress induced by hydrogen peroxide (H2O2). To achieve this goal, freshly isolated human granulosa/luteal cells were maintained in culture. After several passages, the cells were treated with H2O2, which induced apoptosis within 2.5 h, while simultaneous treatment with P4 attenuated the apoptotic action of H2O2. AG 205, a PGRMC1 antagonist, eliminated P4's ability to prevent H2O2-induced apoptosis. AG 205 neither affected PGRMC1's cytoplasmic localization nor its interaction with PGRMC2, but appeared to reduce its presence within the nucleus. AG 205 also (1) increased the monomeric and decreased the higher molecular weight forms of PGRMC1 (i.e., dimers/oligomers) and (2) altered the expression of several genes involved in apoptosis. The most dramatic change was an approximate 8-fold increase in Harakiri (Hrk) mRNA. However, AG 205 did not induce apoptosis in the absence of H2O2. Taken together, these observations suggest that the higher molecular weight forms of PGRMC1 likely account in part for PGRMC1's ability to suppress the expression of Hrk.
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