9t43 | pdb_00009t43
Human PRMT5:MEP50 in complex with AZD3470
Structural highlights
FunctionANM5_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.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] Publication Abstract from PubMedInhibition of the arginine methyltransferase protein arginine methyltransferase 5 (PRMT5) has emerged as a key target for cancer therapy. Leveraging the MTAP synthetic lethality mechanism, MTA-cooperative PRMT5 inhibitors are showing promising potential as precision cancer treatments with a high therapeutic index. Herein, we report our efforts to further optimize our previously reported in vivo tool compound 1 ("AZ-PRMT5i-1") toward a clinical candidate-quality profile, by addressing key shortcomings of this compound horizontal line limited aqueous solubility, low hERG receptor activity, and an unfavorable predicted human dose. Exploration of the terminal lactam substitution group and the central aromatic group of the isindolinone scaffold provided the key structure-activity relationship insights to meet these goals. The highest quality compounds in this series were identified by the use of a dose-to-human (D2H) automated model. These efforts resulted in the identification of 14, which shows the appropriate physicochemical properties, DMPK characteristics, and PRMT5-driven activity to be selected for progression into clinical studies. Use of Human Dose Prediction Metrics to Enable Discovery of AZD3470, an MTA-Cooperative PRMT5 Inhibitor in Clinical Evaluation.,Smith JM, Barlaam B, Beattie D, Bradshaw L, Chan HM, Cooke SL, Cronin A, Cumming I, Dean E, Debreczeni JE, Barco Barrantes ID, Ferguson D, Gianni D, Grondine M, Lynch JT, McWilliams L, Moore S, Raubo P, Qu Y, Robb GR, Tan L, Urosevic J, Vazquez-Chantada M, Wang P J Med Chem. 2026 May 22. doi: 10.1021/acs.jmedchem.6c00659. PMID:42172174[12] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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