1. Academic Validation
  2. MRTX1719 is an MTA-cooperative PRMT5 inhibitor that exhibits synthetic lethality in preclinical models and patients with MTAP deleted cancer

MRTX1719 is an MTA-cooperative PRMT5 inhibitor that exhibits synthetic lethality in preclinical models and patients with MTAP deleted cancer

  • Cancer Discov. 2023 Aug 8;CD-23-0669. doi: 10.1158/2159-8290.CD-23-0669.
Lars D Engstrom 1 Ruth Aranda 2 Laura Waters 1 Krystal Moya 1 Vickie Bowcut 1 Laura Vegar 1 David Trinh 1 Allan Hebbert 1 Christopher R Smith 1 Svitlana Kulyk 3 J David Lawson 1 Leo He 4 Laura D Hover 4 Julio Fernandez-Banet 5 Jill Hallin 2 Darin Vanderpool 1 David M Briere 2 Alice Blaj 1 Matthew A Marx 2 Jordi Rodon 6 Michael Offin 7 Kathryn C Arbour 8 Melissa L Johnson 9 David J Kwiatkowski 10 Pasi A Janne 11 Candace L Haddox 12 Kyriakos P Papadopoulos 13 Jason T Henry 14 Konstantinos Leventakos 15 James G Christensen 2 Ronald Shazer 16 Peter Olson 2
Affiliations

Affiliations

  • 1 Mirati Therapeutics, Inc., San Diego, CA, United States.
  • 2 Mirati Therapeutics (United States), San Diego, CA, United States.
  • 3 Mirati Therapeutics, San Diego, CA, United States.
  • 4 Monoceros Biosciences, LLC, San Diego, CA, United States.
  • 5 Monoceros Biosystems LLC, San Diego, CA, United States.
  • 6 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States.
  • 7 Memorial Sloan Kettering Cancer Center, Hillsdale, NJ, United States.
  • 8 Memorial Sloan Kettering Cancer Center, New York, NY, United States.
  • 9 Sarah Cannon Research Instutite, Nashville, TN, United States.
  • 10 Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States.
  • 11 Dana-Farber Cancer Institute, Boston, Massachusetts, United States.
  • 12 Dana-Farber Cancer Institute, Boston, MA, United States.
  • 13 START, San Antonio, Texas, United States.
  • 14 HealthONE, Denver, CO, United States.
  • 15 Mayo Clinic, United States.
  • 16 Mirati Therapeutics (United States), United States.
Abstract

Previous studies implicated PRMT5 as a synthetic lethal target for MTAP deleted (MTAP del) cancers, however, the pharmacological characterization of small molecule inhibitors that recapitulate the synthetic lethal phenotype have not been described. MRTX1719 selectively inhibited PRMT5 in the presence of MTA, which is elevated in MTAP del cancers, and inhibited PRMT5-dependent activity and cell viability with >70-fold selectivity in HCT116 MTAP del compared to HCT116 MTAP WT cells. MRTX1719 demonstrated dose-dependent anti-tumor activity and inhibition of PRMT5-dependent SDMA modification in MTAP del tumors. In contrast, MRTX1719 demonstrated minimal effects on SDMA and viability in MTAP WT tumor xenografts, mouse or human hematopoietic cells. MRTX1719 demonstrated marked anti-tumor activity across a panel of xenograft models at well-tolerated doses. Early signs of clinical activity were observed including objective responses in patients with MTAP del melanoma, gallbladder adenocarcinoma, mesothelioma, non-small cell lung Cancer, and MPNST from the Phase 1/2 study.

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