9py0

PRMT5 Bound to Compound 12 and MTA

spinqualitylabelsall models 9py0, resolution 2.36Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9py0 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 2.36Å Ligands: A1CMZ, MTA 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 We describe the discovery of a series of potent, selective, and orally bioavailable bis-acyl hydrazide inhibitors targeting the PRMT5.MTA complex for the treatment of MTAP-deleted cancers. Key to this discovery was the identification of major metabolite M1, resulting from N-demethylation of lead inhibitor compound 12, as a potent hERG inhibitor. Leveraging the kinetic isotope effect, we generated methyl-d(3) analog 16 which reduced the formation of M1 in vivo, resulting in acceptable safety margins and an improved pharmacokinetic profile. Our data suggest this strategy could be employed more broadly to reduce undesirable metabolism of methylated amines. Discovery of Bis-Acyl Hydrazides as Potent and Bioavailable MTA-Cooperative PRMT5 Inhibitors: A Case Study of Leveraging the Deuterium Kinetic Isotope Effect.,Debien L, Armstrong MK, Farr JD, Ferrao RD, Gupta PL, Niu C, Anderson AJ, Benner P, Bristol AN, Chin E, Chou C, Deng Y, Fu X, Gheiratmand M, Hull SM, Hung JC, June B, Kirschman JH, Le H, Malik B, Mitchell ML, Mukherjee PK, Nguyen SV, Notte GT, Orf J, Roa DE, Santos R, Schrier AJ, Spence KA, Sura R, Yang ZY, Zane D, Zahabian AN, Zavorotinskaya T J Med Chem. 2025 Dec 22. doi: 10.1021/acs.jmedchem.5c02392. PMID:41429045 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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