MRTX9768: a synthetic lethal-based inhibitor designed to bind the PRMT5•MTA complex and target M...

Dr Matthew Marx speaks to ecancer about Mirati’s study regarding the fragment-based discovery of a synthetic lethal-based inhibitor designed to bind the PRMT5 MTA complex and selectively target MTAP/CDKN2A-deleted tumours. Dr Marx says that MTAP deletion is the most common gene deletion event across several cancer types and is associated with a poor prognosis for patients with this genetic alteration. He explains the rationale of the study; that PRMT5 is an enzyme critical to the survival of both healthy and cancer cells and is partially inhibited by a metabolite called methylthioadenosine (MTA), which specifically accumulates in MTAP-deleted cancers. Dr Marx then discusses the methodology and results of the study. In the preclinical study, the PRMT5 inhibitor was shown to specifically target and stabilise the PRMT5/MTA complex in MTAP-deleted cancer models. This is a targeted approach known as synthetic lethality in which a therapeutic agent selectively kills cells with a particular genetic alteration while having minimal to no effect on healthy cells. In the end, Dr Marx mentions that Mirati is advancing its PRMT5 compound toward an IND filing in the first half of 2022.
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