9n3o
From Proteopedia
Crystal structure of PRMT5:MEP50 in complex with MTA and oxamide compound 14
Structural highlights
FunctionMEP50_HUMAN Non-catalytic component of the 20S PRMT5-containing methyltransferase complex, which modifies specific arginines to dimethylarginines in several spliceosomal Sm proteins and histones. This modification targets Sm proteins to the survival of motor neurons (SMN) complex for assembly into small nuclear ribonucleoprotein core particles. Might play a role in transcription regulation. The 20S PRMT5-containing methyltransferase complex also 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.[1] [2] Publication Abstract from PubMedThe gene encoding for MTAP is one of the most commonly deleted genes in cancer, occurring in approximately 10-15% of all human cancer. We have previously described the discovery of TNG908, a brain-penetrant clinical-stage compound that selectively targets MTAP-deleted cancer cells by binding to and inhibiting PRMT5 cooperatively with MTA, which is present in elevated concentrations in MTAP-deleted cells. Herein we describe the discovery of TNG462, a more potent and selective MTA-cooperative PRMT5 inhibitor with improved DMPK properties that is selective for MTAP-deleted cancers and is currently in Phase I/II clinical trials. Discovery of TNG462: A Highly Potent and Selective MTA-Cooperative PRMT5 Inhibitor to Target Cancers with MTAP Deletion.,Cottrell KM, Briggs KJ, Tsai A, Tonini MR, Whittington DA, Gong S, Liang C, McCarren P, Zhang M, Zhang W, Huang A, Maxwell JP J Med Chem. 2025 Mar 4. doi: 10.1021/acs.jmedchem.4c03067. PMID:40035511[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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