9mre | pdb_00009mre

From DNA-Encoded Library Screening to AM-9747 - an MTA-Cooperative PRMT5 Inhibitor with Potent Oral in vivo Efficacy

spinqualitylabelsall models 9mre, resolution 2.25Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9mre is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.25Å Ligands: A1BQW, DMS, GOL, MTA, PEG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function ANM5_HUMAN Arginine methyltransferase that can both catalyze the formation of omega-N monomethylarginine (MMA) and symmetrical dimethylarginine (sDMA), with a preference for the formation of MMA. Specifically mediates the symmetrical dimethylation of arginine residues in the small nuclear ribonucleoproteins Sm D1 (SNRPD1) and Sm D3 (SNRPD3); such methylation being required for the assembly and biogenesis of snRNP core particles. Methylates SUPT5H. Mono- and dimethylates arginine residues of myelin basic protein (MBP) in vitro. Plays a role in the assembly of snRNP core particles. May play a role in cytokine-activated transduction pathways. Negatively regulates cyclin E1 promoter activity and cellular proliferation. May regulate the SUPT5H transcriptional elongation properties. May be part of a pathway that is connected to a chloride current, possibly through cytoskeletal rearrangement. Methylates histone H2A and H4 'Arg-3' during germ cell development. Methylates histone H3 'Arg-8', which may repress transcription. Methylates the Piwi proteins (PIWIL1, PIWIL2 and PIWIL4), methylation of Piwi proteins being required for the interaction with Tudor domain-containing proteins and subsequent localization to the meiotic nuage. Methylates RPS10. Attenuates EGF signaling through the MAPK1/MAPK3 pathway acting at 2 levels. First, monomethylates EGFR; this enhances EGFR 'Tyr-1197' phosphorylation and PTPN6 recruitment, eventually leading to reduced SOS1 phosphorylation. Second, methylates RAF1 and probably BRAF, hence destabilizing these 2 signaling proteins and reducing their catalytic activity. Required for induction of E-selectin and VCAM-1, on the endothelial cells surface at sites of inflammation. Methylates HOXA9. Methylates and regulates SRGAP2 which is involved in cell migration and differentiation. Acts as a transcriptional corepressor in CRY1-mediated repression of the core circadian component PER1 by regulating the H4R3 dimethylation at the PER1 promoter. Publication Abstract from PubMed Inhibition of the methyltransferase enzyme PRMT5 by MTA accumulation is a vulnerability of MTAP-deleted cancers. Herein, we report the discovery and optimization of a quinolin-2-amine DEL hit that cooperatively binds PRMT5:MEP50 and MTA to generate a catalytically inhibited ternary complex. X-ray crystallography confirms quinolin-2-amine binding of PRMT5 glutamate-444, while simultaneously exhibiting a hydrophobic interaction with MTA. Lead optimization produced AM-9747, which selectively inhibits PRMT5-directed symmetric dimethylation of arginine residues of proteins, leading to a potent reduction of cell viability in MTAP-del cells compared to MTAP-WT cells. Once-daily oral dosing of AM-9747 in mouse xenografts is well tolerated, displaying a robust and dose-dependent inhibition of symmetric dimethylation of arginine in MTAP-del tumor-xenografts and significant concomitant tumor growth inhibition without any significant effect on MTAP-WT tumor xenografts. From DNA-Encoded Library Screening to AM-9747: An MTA-Cooperative PRMT5 Inhibitor with Potent Oral In Vivo Efficacy.,Sarvary I, Vestergaard M, Moretti L, Andersson J, Peiro Cadahia J, Cowland S, Flagstad T, Franch T, Gouliaev A, Husemoen G, Jacso T, Kronborg T, Kuropatnicka A, Nadali A, Madsen M, Nielsen SR, Pii D, Ryborg SR, Soede C, Allen JR, Bourbeau M, Li K, Liu Q, Lo MC, Madoux F, Mardirossian N, Moriguchi J, Ngo R, Peng CC, Pettus L, Tamayo N, Wang P, Kapoor R, Belmontes B, Caenepeel S, Hughes P, Liu S, Slemmons KK, Yang Y, Xie F, Ghimire-Rijal S, Mukund S, Glad S J Med Chem. 2025 Mar 18. doi: 10.1021/acs.jmedchem.4c03101. PMID:40102181 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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