Overview

MRTX-1719 is a novel small-molecule inhibitor targeting Protein Arginine Methyltransferase 5 (PRMT5), an enzyme crucial for adding symmetric dimethylarginine (SDMA) posttranslational modifications to various cellular proteins involved in essential functions like RNA splicing, transcription, and translation. Specifically, PRMT5 requires the cofactor MEP50 and utilizes S-adenosyl methionine (SAM) as the methyl donor to perform its catalytic function. The significance of MRTX-1719 lies in its synthetic lethality effect observed in cancers with homozygous deletion of the MTAP gene (MTAP del cancers), frequently found in various cancer types including non–small cell lung cancer, mesothelioma, and pancreatic cancer, among others.

Applications as Antitumor Agents

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. 1

Dynamic Kinetic Resolution

A high-yielding protocol for atropisomeric resolution was developed by rectifying incompatibilities between crystallization and epimerization via continuous processing. Application toward synthesis of MRTX1719, a densely functionalized active pharmaceutical ingredient (API), improved yield from 37% to 87%. This protocol provides a complementary means to access rotamers which challenge current asymmetric methodologies, and greatly improves sustainability by decreasing the consumption of solvent and advanced synthetic intermediates.2

Reference

1. Engstrom LD, Aranda R, Waters L, et al. MRTX1719 Is an MTA-Cooperative PRMT5 Inhibitor That Exhibits Synthetic Lethality in Preclinical Models and Patients with MTAP-Deleted Cancer. Cancer Discov. 2023; 13(11): 2412-2431.

2. Achmatowicz MM, Chen CY, Snead DR. Developing an atroposelective dynamic kinetic resolution of MRTX1719 by resolving incompatible chemical operations. Chem Commun (Camb). 2022; 58(74): 10365-10367.