MTA-Cooperative PRMT5 Inhibitor

(MRTX1719)

Mirati is advancing new research to address MTAP-deleted cancers with the goal of providing a potentially novel treatment option both as a monotherapy and in combination with other agents.

(MRTX1719)

Mirati is advancing new research to address MTAP-deleted cancers with the goal of providing a potentially novel treatment option both as a monotherapy and in combination with other agents.

Introduction

Researchers continue to look for new targeted therapies for genetically defined-cancers, including cancers with methylthioadenosine phosphorylase (MTAP) deletion.^17,18,19 MTAP deletions occur in around 10 percent of cancers,²⁰ and are associated with a poor prognosis, representing a significant unmet medical need.

Mirati is advancing new research to address MTAP-deleted cancers with the goal of providing a potentially novel treatment option both as a monotherapy and in combination with other agents.

Scientific Rationale

Cancer cells with MTAP deletion are highly sensitive to inhibition of protein arginine methyltransferase 5 (PRMT5).^17,18,19 This is an example of synthetic lethality where the blocking of two genes results in cell death.

MTAP deletion results in the accumulation of methylthioadenosine (MTA) within cancer cells. The MTA binds to PRMT5 to form the PRMT5-MTA complex. This new complex creates a novel drug target for the treatment of MTAP-deleted cancers.

Mirati’s internally-discovered compound, MRTX1719, selectively seeks out and binds the PRMT5-MTA complex selectively inhibiting PRMT5 function in MTAP-deleted cancer cells. MRTX1719 selectively inhibits viability of cancer cells with MTAP deletion and is designed to spare healthy, non-tumor cells.²¹ This differentiated approach demonstrates a potentially improved therapeutic index in preclinical studies relative to first generation PRMT5 inhibitors.

MRTX1719 Mechanism of Action