A patent review of MAT2a inhibitors (2018–2021)

ABSTRACT

Introduction

In methylthioadenosine phosphorylase (MTAP)-deficient tumor cells, reduced S-adenosylmethionine (SAM) levels in the context of elevated methylthioadenosine (MTA) has been hypothesized to lead to inhibition of protein arginine methyltransferase 5 (PRMT5) and tumor growth inhibition. Inhibitors of methionine adenosyltransferase 2A (MAT2a) prevent the synthesis of SAM from methionine and have therefore attracted increasing attention as potential chemotherapeutic agents in cancers characterized by MTAP-loss.

Areas covered

This review covers patent applications between January 2018 and December 2021. 18 patent applications from 5 different applicants are evaluated.

Expert opinion

Recent advances in the field show a significant interest in the MAT2a therapeutic hypothesis. Agios and Ideaya in particular have capitalized on an allosteric binding mode first published by Pfizer in at least two of the filings during this time period, leading to potent, selective inhibitors. They have advanced MAT2a inhibitors to phase I clinical studies to explore their benefit to patients suffering with MTAP-deficient solid tumors or lymphoma. Whilst the other patent disclosures during this time frame have not led to disclosed candidates, the trials initiated by Agios and Ideaya studies will clearly inform on the potential for such inhibitors as viable therapeutic agents either as single agent or in combination.

KEYWORDS:

• MAT2a
• PRMT5
• MTAP
• cancer
• chemotherapy
• allosteric

Article highlights

• Inhibition of MAT2a has emerged as an intriguing way to exploit a collateral vulnerability of MTAP-deficient tumor cells, by indirectly inhibiting PRMT5 through reduction of its co-substrate SAM against a background of elevated MTA levels.

• Following the disclosure of an initial ligand PF-9366, that was shown to be capable of MAT2a inhibition, a number of structurally diverse chemotypes have been disclosed that are capable of inhibiting MAT2a.

• Patent applications describing MAT2a inhibitors from January 2018 to December 2021 are collated and analysed in this article. The material covers 18 applications from 5 different applicants.

• Ongoing research into this target has culminated in the first candidates entering the clinic. At the time of writing, two molecules (AG-270 & IDEA-397) have advanced into clinical trials and these should provide valuable clinical feedback on the therapeutic potential of MAT2a inhibition in the treatment of MTAP deleted cancers.

Acknowledgments

Thanks to Sandhya Deo and Mathew Leese for constructive comments on the manuscript.

Declaration of interests

SJ Atkinson, L Evans and JS Scott are full time employees of AstraZeneca. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

SJA, LE and JSS all contributed to primary patent research and data extraction and each wrote at least one of the main body sections divided by company patent applications. JSS wrote the introduction and SJA collated the document and wrote the conclusion and expert opinion sections.

Additional information

Funding

This paper was funded by AstraZeneca