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.

中文翻译：

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MAT2a抑制剂的专利审查（2018-2021）

摘要

介绍

在甲基硫腺苷磷酸化酶 (MTAP) 缺陷的肿瘤细胞中，假设在甲基硫腺苷 (MTA) 升高的情况下 S-腺苷甲硫氨酸 (SAM) 水平降低会导致蛋白精氨酸甲基转移酶 5 (PRMT5) 的抑制和肿瘤生长抑制。甲硫氨酸腺苷转移酶 2A (MAT2a) 的抑制剂可阻止甲硫氨酸合成 SAM，因此作为以 MTAP 缺失为特征的癌症的潜在化疗药物而受到越来越多的关注。

涵盖的领域

本次审查涵盖 2018 年 1 月至 2021 年 12 月期间的专利申请。评估了来自 5 个不同申请人的 18 项专利申请。

专家意见

该领域的最新进展显示出人们对 MAT2a 治疗假说的浓厚兴趣。尤其是 Agios 和 Ideaya 在此期间至少在两份申请中利用了辉瑞首次公布的变构结合模式，从而产生了有效的选择性抑制剂。他们已将 MAT2a 抑制剂推进到 I 期临床研究，以探索它们对患有 MTAP 缺陷实体瘤或淋巴瘤的患者的益处。虽然在此期间披露的其他专利并未导致候选药物的披露，但由 Agios 和 Ideaya 研究发起的试验将清楚地表明此类抑制剂作为单一药物或联合药物作为可行治疗剂的潜力。