Fragment-Based Discovery of MRTX1719, a Synthetic Lethal Inhibitor of the PRMT5•MTA Complex for the Treatment of -Deleted Cancers.

Publication Type:

Journal Article

Authors:

Smith, Christopher R; Aranda, Ruth; Bobinski, Thomas P; Briere, David M; Burns, Aaron C; Christensen, James G; Clarine, Jeffery; Engstrom, Lars D; Gunn, Robin J; Ivetac, Anthony; Jean-Baptiste, Ronald; Ketcham, John M; Kobayashi, Masakazu; Kuehler, Jon; Kulyk, Svitlana; Lawson, J David; Moya, Krystal; Olson, Peter; Rahbaek, Lisa; Thomas, Nicole C; Wang, Xiaolun; Waters, Laura M; Marx, Matthew A

Source:

J Med Chem (2022)

Abstract:

<p>The PRMT5&bull;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&bull;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&bull;MTA complex. Fragment growth supported by structural insights from X-ray crystallography coupled with optimization of pharmacokinetic properties aided the discovery of development candidate .</p>

PDB: 
F1 (PDB 7S0U), 9 (PDB 7S1Q), MRTX1719 (PDB 7S1S), 29 (PDB 7SES), 30 (PDB 7SER), (M)-31 (PDB 7S1R) bound to PRMT5•MTA, and the PRMT5•sinefungin structure (PDB 7S1P)
Detector: 
EIGER
EIGER2
Beamline: 
24-ID-C
24-ID-E