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

  • J Med Chem. 2022 Feb 10;65(3):1749-1766. doi: 10.1021/acs.jmedchem.1c01900.
Christopher R Smith  1 ,  Ruth Aranda  1 ,  Thomas P Bobinski  2 ,  David M Briere  1 ,  Aaron C Burns  1 ,  James G Christensen  1 ,  Jeffery Clarine  1 ,  Lars D Engstrom  1 ,  Robin J Gunn  1 ,  Anthony Ivetac  1 ,  Ronald Jean-Baptiste  3 ,  John M Ketcham  1 ,  Masakazu Kobayashi  3 ,  Jon Kuehler  1 ,  Svitlana Kulyk  1 ,  J David Lawson  1 ,  Krystal Moya  1 ,  Peter Olson  1 ,  Lisa Rahbaek  1 ,  Nicole C Thomas  1 ,  Xiaolun Wang  1 ,  Laura M Waters  1 ,  Matthew A Marx  1
Affiliations
  • 1. Mirati Therapeutics, San Diego, California 92121, United States.
  • 2. DSG, San Diego, California 92130, United States.
  • 3. ZoBio BV, J. H. Oortweg 19, 2333 CH Leiden, Netherlands.
PMID: 35041419 DOI: 10.1021/acs.jmedchem.1c01900
Abstract

The PRMT5•MTA complex has recently emerged as a new synthetically lethal drug target for the treatment of MTAP-deleted cancers. Here, we report the discovery of development candidate MRTX1719. MRTX1719 is a potent and selective binder to the PRMT5•MTA complex and selectively inhibits PRMT5 activity in MTAP-deleted cells compared to MTAP-wild-type cells. Daily oral administration of MRTX1719 to tumor xenograft-bearing mice demonstrated dose-dependent inhibition of PRMT5-dependent symmetric dimethylarginine protein modification in MTAP-deleted tumors that correlated with antitumor activity. A 4-(aminomethyl)phthalazin-1(2H)-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 MRTX1719.

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