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

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

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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