| Structural highlights
9n3o 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 2.37Å |
| Ligands: | , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
MEP50_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 PubMed
The 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
- ↑ Friesen WJ, Wyce A, Paushkin S, Abel L, Rappsilber J, Mann M, Dreyfuss G. A novel WD repeat protein component of the methylosome binds Sm proteins. J Biol Chem. 2002 Mar 8;277(10):8243-7. Epub 2001 Dec 26. PMID:11756452 doi:http://dx.doi.org/10.1074/jbc.M109984200
- ↑ Antonysamy S, Bonday Z, Campbell RM, Doyle B, Druzina Z, Gheyi T, Han B, Jungheim LN, Qian Y, Rauch C, Russell M, Sauder JM, Wasserman SR, Weichert K, Willard FS, Zhang A, Emtage S. Crystal structure of the human PRMT5:MEP50 complex. Proc Natl Acad Sci U S A. 2012 Oct 30;109(44):17960-5. doi:, 10.1073/pnas.1209814109. Epub 2012 Oct 15. PMID:23071334 doi:http://dx.doi.org/10.1073/pnas.1209814109
- ↑ Cottrell KM, Briggs KJ, Tsai A, Tonini MR, Whittington DA, Gong S, Liang C, McCarren P, Zhang M, Zhang W, Huang A, Maxwell JP. Discovery of TNG462: A Highly Potent and Selective MTA-Cooperative PRMT5 Inhibitor to Target Cancers with MTAP Deletion. J Med Chem. 2025 Mar 4. PMID:40035511 doi:10.1021/acs.jmedchem.4c03067
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