General Description

MRTX-1719 is a novel small-molecule inhibitor targeting PRMT5, crucial for SDMA modifications in cellular proteins. It exploits synthetic lethality in MTAP del cancers by selectively inhibiting PRMT5, offering tumor regression potential with reduced toxicities. As an antitumor agent, MRTX-1719 demonstrates enhanced stability and inhibitory activity, with a versatile molecular structure adaptable to various cancer types. Its pharmaceutical formulation ensures optimal bioavailability, while clinical applications span a wide range of cancers. The atroposelective dynamic kinetic resolution of MRTX-1719 enhances synthesis efficiency and sustainability, providing a high-yielding protocol for resolving atropisomers. Overall, MRTX-1719 represents a cutting-edge PRMT5-MTA inhibitor with significant therapeutic promise in cancer treatment.

Figure 1. MRTX-1719

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. MTAP loss leads to the accumulation of 5′-deoxy-5′-methylthioadenosine (MTA), which competitively inhibits PRMT5 activity. MRTX-1719 exploits this vulnerability by selectively inhibiting PRMT5 in MTAP del cancer cells, inducing synthetic lethality. Unlike previous PRMT5 inhibitors, MRTX-1719 binds to PRMT5 complexed with MTA, exhibiting greater selectivity and efficacy against MTAP del cancer cells while minimizing off-target toxicities. This specificity is crucial for achieving the necessary target inhibition levels for tumor regression while avoiding mechanism-based toxicities observed with earlier inhibitors. In summary, MRTX-1719 represents a promising therapeutic approach for MTAP del cancers by exploiting the synthetic lethality relationship between PRMT5 inhibition and MTAP loss, offering potential for improved efficacy and reduced side effects compared to existing PRMT5 inhibitors. ¹

Applications as Antitumor Agents

MRTX-1719, a protein arginine methyltransferase 5-methylthioadenosine (PRMT5-MTA) inhibitor, represents a promising advancement in the field of antitumor agents. With enhanced protein stability, cell proliferation suppression, and potent inhibitory activity, MRTX-1719 offers a multifaceted approach to combat various types of cancers. Through meticulous chemical design, MRTX-1719, represented by compound I, demonstrates a versatile molecular structure adaptable to different cancer types. Its composition, including substituents like C1-6 alkyl, haloalkyl, amino, CN, OH, and cycloalkyl, among others, enables precise targeting of PRMT5-MTA, a crucial enzyme involved in cancer progression. Moreover, MRTX-1719's pharmaceutical formulation, comprising pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates, or solvates, ensures optimal bioavailability and therapeutic efficacy. This comprehensive approach extends to the preparation process, involving multiple steps to synthesize the compound efficiently. Clinical applications of MRTX-1719 encompass a broad spectrum of cancers, including Acoustic neuroma, adenocarcinoma, adrenal cancer, anal cancer, and angiosarcoma, among others. By specifically targeting PRMT5-MTA, MRTX-1719 disrupts crucial cellular processes implicated in tumor growth and metastasis, offering a promising avenue for cancer treatment. In summary, MRTX-1719 represents a cutting-edge PRMT5-MTA inhibitor with immense potential as an antitumor agent, showcasing both scientific innovation and therapeutic promise in the fight against cancer. ²

Dynamic Kinetic Resolution

The atroposelective dynamic kinetic resolution of MRTX-1719 involves a novel approach to resolving incompatible chemical operations. By addressing issues between crystallization and epimerization through continuous processing, a high-yielding protocol for atropisomeric resolution is achieved. This advancement significantly enhances the synthesis of MRTX-1719, an intricate active pharmaceutical ingredient (API), boosting yield from 37% to 87%. Notably, this protocol offers a complementary avenue for accessing rotamers that pose challenges to existing asymmetric methodologies. Moreover, it promotes sustainability by reducing solvent consumption and the need for advanced synthetic intermediates. ³

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. Gao F, Liu B, Jing LD, et al. Protein arginine methyltransferase 5-methylthioadenosine (PRMT5-MTA) inhibitor and application as antitumor agents. 2023; Patent Number: CN116178347.

3. 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.