8VET
Crystal structure of PRMT5:MEP50 in complex with MTA and oxamide compound 1
This is a non-PDB format compatible entry.
Summary for 8VET
| Entry DOI | 10.2210/pdb8vet/pdb |
| Descriptor | Protein arginine N-methyltransferase 5, Methylosome protein 50, 5'-DEOXY-5'-METHYLTHIOADENOSINE, ... (7 entities in total) |
| Functional Keywords | mtap-null, sam, mta, mta-cooperative, transferase, transferase-inhibitor complex, transferase/inhibitor |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 2 |
| Total formula weight | 112347.28 |
| Authors | Whittington, D.A. (deposition date: 2023-12-20, release date: 2024-04-24, Last modification date: 2024-05-08) |
| Primary citation | Cottrell, K.M.,Briggs, K.J.,Whittington, D.A.,Jahic, H.,Ali, J.A.,Davis, C.B.,Gong, S.,Gotur, D.,Gu, L.,McCarren, P.,Tonini, M.R.,Tsai, A.,Wilker, E.W.,Yuan, H.,Zhang, M.,Zhang, W.,Huang, A.,Maxwell, J.P. Discovery of TNG908: A Selective, Brain Penetrant, MTA-Cooperative PRMT5 Inhibitor That Is Synthetically Lethal with MTAP -Deleted Cancers. J.Med.Chem., 67:6064-6080, 2024 Cited by PubMed Abstract: It has been shown that PRMT5 inhibition by small molecules can selectively kill cancer cells with homozygous deletion of the gene if the inhibitors can leverage the consequence of deletion, namely, accumulation of the MTAP substrate MTA. Herein, we describe the discovery of TNG908, a potent inhibitor that binds the PRMT5·MTA complex, leading to 15-fold-selective killing of -deleted (MTAP-null) cells compared to intact (MTAP WT) cells. TNG908 shows selective antitumor activity when dosed orally in mouse xenograft models, and its physicochemical properties are amenable for crossing the blood-brain barrier (BBB), supporting clinical study for the treatment of both CNS and non-CNS tumors with loss. PubMed: 38595098DOI: 10.1021/acs.jmedchem.4c00133 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.63 Å) |
Structure validation
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