7S1P

PRMT5/MEP50 crystal structure with sinefungin bound

Summary for 7S1P

• Entry DOI: 10.2210/pdb7s1p/pdb
• Related: 7S0U 7S1Q 7S1R 7S1S 7SER 7SES
• Descriptor: Protein arginine N-methyltransferase 5, Methylosome protein 50, SINEFUNGIN, ... (4 entities in total)
• Functional Keywords: prmt5, mtap, mta, methyl transferase, collateral lethality, synthetic lethality, fragment-based lead discovery, transferase, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 112007.42

Authors

Gunn, R.J.,Thomas, N.C.,Lawson, J.D.,Ivetac, A.,Kulyk, S.,Smith, C.R.,Marx, M.A. (deposition date: 2021-09-02, release date: 2022-03-16, Last modification date: 2023-10-18)

Primary citation

Smith, C.R.,Aranda, R.,Bobinski, T.P.,Briere, D.M.,Burns, A.C.,Christensen, J.G.,Clarine, J.,Engstrom, L.D.,Gunn, R.J.,Ivetac, A.,Jean-Baptiste, R.,Ketcham, J.M.,Kobayashi, M.,Kuehler, J.,Kulyk, S.,Lawson, J.D.,Moya, K.,Olson, P.,Rahbaek, L.,Thomas, N.C.,Wang, X.,Waters, L.M.,Marx, M.A.
Fragment-Based Discovery of MRTX1719, a Synthetic Lethal Inhibitor of the PRMT5•MTA Complex for the Treatment of MTAP -Deleted Cancers.
J.Med.Chem., 65:1749-1766, 2022

PubMed Abstract: The PRMT5•MTA complex has recently emerged as a new synthetically lethal drug target for the treatment of -deleted cancers. Here, we report the discovery of development candidate . is a potent and selective binder to the PRMT5•MTA complex and selectively inhibits PRMT5 activity in -deleted cells compared to -wild-type cells. Daily oral administration of to tumor xenograft-bearing mice demonstrated dose-dependent inhibition of PRMT5-dependent symmetric dimethylarginine protein modification in -deleted tumors that correlated with antitumor activity. A 4-(aminomethyl)phthalazin-1(2)-one hit was identified through a fragment-based screen, followed by X-ray crystallography, to confirm binding to the PRMT5•MTA complex. Fragment growth supported by structural insights from X-ray crystallography coupled with optimization of pharmacokinetic properties aided the discovery of development candidate .

PubMed: 35041419
DOI: 10.1021/acs.jmedchem.1c01900

Experimental method

X-RAY DIFFRACTION (2.21 Å)