articleCancer DiscoveryAug 8, 2023HYBRID OA

MRTX1719 Is an MTA-Cooperative PRMT5 Inhibitor That Exhibits Synthetic Lethality in Preclinical Models and Patients with MTAP -Deleted Cancer

LDLars D. EngstromRARuth ArandaLWLaura WatersKMKrystal MoyaVBVickie Bowcut

Mirati Therapeutics (United States) · Neurocrine Biosciences (United States) · +10 more institutions

PubMed
Indexed incrossrefpubmed

Abstract

Previous studies implicated protein arginine methyltransferase 5 (PRMT5) as a synthetic lethal target for MTAP-deleted (MTAP del) cancers; however, the pharmacologic characterization of small-molecule inhibitors that recapitulate the synthetic lethal phenotype has 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 selecti-vity in HCT116 MTAP del compared with HCT116 MTAP wild-type (WT) cells. MRTX1719 demonstrated dose-dependent antitumor activity and inhibition of PRMT5-dependent SDMA modification in MTAP del tumors. In contrast, MRTX1719 demonstrated minimal effects on…

Citation impact

187
total citations
FWCI
27.18
Percentile
100%
References
32
Citations per year

Authors

32

Topics & keywords

Topics
Keywords
  • Protein arginine methyltransferase 5
  • Synthetic lethality
  • Cancer research
  • Cancer
  • Medicine
  • Melanoma
  • Biology
  • Methyltransferase
UN Sustainable Development Goals
  • Good health and well-being
No related works found for this paper.

Funding