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

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 SDMA and viability in MTAP WT tumor xenografts or hematopoietic cells. MRTX1719 demonstrated marked antitumor 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 malignant peripheral nerve sheath tumors from the phase I/II study.

 

Comments:

That's an intriguing study! It seems like MRTX1719 exhibits promising characteristics as a selective inhibitor of PRMT5 in MTAP-deleted cancers. Its ability to target PRMT5-dependent activities and viability specifically in MTAP-deleted cells, while sparing MTAP wild-type cells, holds significant therapeutic potential.

The findings regarding the dose-dependent antitumor activity of MRTX1719 and its effectiveness in inhibiting PRMT5-dependent SDMA modification in MTAP-deleted tumors are particularly encouraging. Moreover, the observed minimal impact on MTAP wild-type tumor xenografts or hematopoietic cells suggests a degree of selectivity that could enhance its safety profile.

The diverse spectrum of cancers showing objective responses in the clinical study, including melanoma, gallbladder adenocarcinoma, mesothelioma, non-small cell lung cancer, and malignant peripheral nerve sheath tumors, further emphasizes the potential broad applicability of MRTX1719 across various cancer types with MTAP deletions.

It appears that MRTX1719 holds promise as a therapeutic agent in MTAP-deleted cancers, demonstrating early signs of clinical activity and potentially paving the way for future targeted therapies in these specific cancer subtypes.

Related Products

Cat.No.	Product Name	Information
E1024	MRTX1719	MRTX1719 is a potent, selective inhibitor of the protein arginine methyltransferase 5·methylthioadenosine phosphorylase complex (PRMT5•MTA), a potentially tumor-selective target for therapeutic intervention.

Related Targets

PRMT