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

Lars D Engstrom1, Ruth Aranda1, Laura Waters1

  • 1Mirati Therapeutics, Inc., San Diego, California.

Cancer Discovery
|August 8, 2023
PubMed

Insights

A new drug, MRTX1719, shows promise as a targeted therapy for cancers with a specific genetic deletion (MTAP del). It selectively inhibits the PRMT5 protein, crucial for cancer cell survival, with early signs of clinical activity observed in patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Protein arginine methyltransferase 5 (PRMT5) is a synthetic lethal target in methylthioadenosine phosphorylase-deleted (MTAP del) cancers.
  • Existing PRMT5 inhibitors lack selectivity for MTAP del genotypes.
  • Elevated methylthioadenosine (MTA) in MTAP del cancers presents a therapeutic window.

Purpose of the Study:

  • To pharmacologically characterize MRTX1719, a novel small-molecule inhibitor targeting PRMT5.
  • To evaluate the selective inhibition of PRMT5 and its downstream effects in MTAP del cancer models.
  • To assess the antitumor activity and safety of MRTX1719 in preclinical and early clinical settings.

Main Methods:

  • In vitro assays assessing PRMT5 inhibition and cell viability in MTAP del versus wild-type (WT) cells.
  • In vivo studies using xenograft models of MTAP del and WT tumors.
  • Pharmacodynamic analysis of PRMT5-dependent symmetric dimethylarginine (SDMA) modification.
  • Phase I/II clinical trial evaluating MRTX1719 in patients with various cancer types.

Main Results:

  • MRTX1719 demonstrated >70-fold selectivity for inhibiting PRMT5 activity and cell viability in MTAP del cells compared to MTAP WT cells.
  • MRTX1719 showed dose-dependent antitumor activity and suppressed PRMT5-dependent SDMA modification in MTAP del tumors.
  • Minimal effects on SDMA and viability were observed in MTAP WT tumors and hematopoietic cells.
  • Marked antitumor activity was observed across multiple xenograft models at well-tolerated doses.
  • Early clinical activity, including objective responses, was noted in patients with MTAP del melanoma, gallbladder adenocarcinoma, mesothelioma, non-small cell lung cancer, and malignant peripheral nerve sheath tumors.

Conclusions:

  • MRTX1719 selectively targets PRMT5 by leveraging elevated MTA in MTAP del cancers.
  • This differentiated binding mode offers a promising therapeutic strategy for the approximately 10% of cancer patients with the MTAP del biomarker.
  • MRTX1719 exhibits significant antitumor efficacy and a favorable safety profile, warranting further clinical investigation.

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