9pca | pdb_00009pca
HUMAN PRMT5:MEP50 COMPLEX IN COMPLEX WITH LIGAND 18
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 PubMedLoss of the functional Adenomatous Polyposis Coli (APC-LOF) tumor suppressor gene represents the disease-initiating event in most colorectal cancer (CRC) cases. A newly identified dependency between PRMT5 and APC-LOF suggests that inhibiting PRMT5 may help intercept CRC. To circumvent hematological toxicities associated with orally bioavailable first-generation PRMT5 inhibitors, we aimed to limit systemic exposure after oral administration. We describe our efforts, challenges, and compound evaluation workflow resulting in gut-restricted PRMT5 inhibitors. A two-pronged approach was envisioned, consisting of (1) minimizing passive absorption, and (2) maximizing systemic clearance by incorporation of a metabolic "soft spot". This resulted in 9 and 18, displaying low absorption in preclinical species and high first-pass extraction mediated by aldehyde oxidase. 9 and 18 demonstrated in vivo colon pharmacodynamics without signs of systemic on-target toxicity, confirming gut-restriction. Administering 9 to dextran sodium sulfate (DSS)-treated polyp-bearing Apc(Min/+) mice significantly reduced polyp number, indicating local treatment efficacy. Discovery of Gut-Restricted PRMT5 Inhibitors to Intercept Colorectal Cancer in Patients with Genetic Loss of Tumor Suppressor Adenomatous Polyposis Coli.,Hulpia F, Schepens W, Lepri S, Nicolai J, Jiang Z, Boj SF, Bush TL, Carvalho MA, Chen F, Chu G, Clancy KW, Etwebi Z, Everaerts M, Fan Y, Fernandez Candelaria FO, Francis A, Hixon MS, Jardi F, Jin S, Larin EM, Last S, Leenaerts JE, Li S, Liddane AG, Lutter FH, Lv D, Mattson B, Milligan CM, Patrick AN, Patwardhan GA, Perez-Benito L, Pieters S, Renders E, Retzbach E, Smith-Monroy C, Silva J, Silva M, Sterckx H, Ten Hag G, Thate C, Van Brandt S, Verissimo CS, Verniest G, Vesely E, Vetrano I, Vinken P, Wang Y, Wong V, Yao X, Yang J, Zijlmans R, Bachman KE, Pocalyko D, Jimenez JM, Gaffney D, Thuring JW J Med Chem. 2025 Aug 26. doi: 10.1021/acs.jmedchem.5c00830. PMID:40857667[12] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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