MRTX9768: a synthetic lethal-based inhibitor designed to bind the PRMT5 MTA complex and target MTAP/CDKN2A-deleted tumours

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Published: 30 Apr 2021
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Dr Matthew Marx - Mirati Therapeutics, San Diego, USA

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.
 

MRTX9768: a synthetic lethal-based inhibitor designed to bind the PRMT5 MTA complex and target MTAP/CDKN2A-deleted tumours

Dr Matthew Marx - Mirati Therapeutics, San Diego, USA

Last weekend at the virtual AACR meeting we presented our initial preclinical data on our internally discovered potentially first in class approach targeting PRMT5. Our goal, the rationale for this project, is a precision medicine to treat patients with MTAP-deleted cancers. The MTAP deletion is the most common gene deletion across all cancer types and is associated with a very poor prognosis for these patients so new treatments are needed.

First, just a little bit more about PRMT5. PRMT5 is an enzyme that is critical to the survival of both healthy and cancer cells. This enzyme is partially inhibited by a metabolite, methylthioadenosine or MTA, which specifically accumulates only in those cancer cells with an MTAP deletion. So our unique approach, which is represented by the data we showed with MRTX9768 at the AACR meeting, is to specifically and selectively target this PRMT5 MTA complex in those MTAP deleted cancers. So in preclinical studies this molecule demonstrated potent and selective inhibition of cellular growth in vitro and reduction of tumour growth in vivo in those MTAP deleted cancer cells.

This is a preclinical programme and our approach was unprecedented so that required that we develop some basic science and novel project plans to advance it. My colleagues, the great scientists here at Mirati Therapeutics, created, prepared and evaluated several hundreds of new molecules in pursuit of this project over the course of the past several years. The significant medical need is a real motivator for us and our desire is to bring hope to patients with these cancers.

Our targeted approach represents the concept of synthetic lethality and in this case the therapeutic agent will selectively kill cancer cells only in the presence of a particular gene alteration in those same cancer cells, in this case the MTAP deletion. This will only have a minimal effect on the healthy cells. The preclinical data that we showed at the AACR meeting this past weekend supports this hypothesis – MRTX9768 is a molecule that achieves these desired outcomes in those preclinical studies. So our next step would be to advance this programme to clinical trials.

Mirati is advancing its PRMT5 lead compound towards an IND filing in the first half of 2022 and we’re very excited to be making this scientific progress for patients with cancer, particularly those patients who have MTAP deleted cancers.
Since the principal of this drug is based on synthetic lethality, would it work in the same way as PARPs?

The PARP inhibitors are the classic example of the approach using synthetic lethality. In this case the MTAP deleted cancers can be specifically identified in patients and they will represent their own unique subset of patients. But the scientific concept that supports our approach, the synthetic lethality concept, is exemplified by PARP inhibitors.

Is there anything you would like to add?

Thank you for the chance to share about our work at Mirati. I want to thank the patients who inspire us and the scientific team here at Mirati for doing such great work.