Targeting the methionine−methionine adenosyl transferase 2A−S-adenosyl methionine axis for cancer therapy

Abstract

Purpose of reviewIn this review, we summarize the biological roles of methionine, methionine adenosyl transferase 2A (MAT2A) and S-adenosyl methionine (SAM) in methylation reactions during tumorigenesis. Newly emerged inhibitors targeting the methionineÀMAT2AÀSAM axis will be discussed. Recent findingsSAM is the critical and global methyl-donor for methylation reactions regulating gene expression, and in mammalian cells, it is synthesized by MAT2A using methionine. Recent studies have validated methionine and MAT2A as metabolic dependencies of cancer cells because of their essential roles in SAM biosynthesis. MAT2A inhibition leads to synthetic lethality in methylthioadenosine-phosphorylase (MTAP)deleted cancers, which accounts for 15% of all cancer types. Of note, remarkable progress has been made in developing inhibitors targeting the methionineÀMAT2AÀSAM axis, as the first-in-class MAT2A inhibitors AG-270 and IDE397 enter clinical trials to treat cancer.

Design and Structural Optimization of Methionine Adenosyltransferase 2A (MAT2A) Inhibitors with High In Vivo Potency and Oral Bioavailability

“…As shown in Table 1, we utilized pyrido [2,3d]pyrimidine as a bicyclic core structure and screened several tricyclic substituents (4−11). Gratifyingly, substitution with methyl-tetrahydrobenzo [4,5]imidazo[1,2-a]pyrazine resulted in a compound (8) with a MAT2A enzymatic inhibition IC 50 of 18 nM and HCT116(MTAP−/−) cell proliferation inhibition IC 50 of 52 nM, which were significantly better than those of AG-270 (cell IC 50 = 244 nM), which is under evaluation in clinical trials (Figure S1). AGI-43192 is a promising clinical candidate developed by Agios Pharmaceuticals.…”

“…1 H NMR (500 MHz, chloroform-d) δ 8.76 (s, 1H), 7.79 (s, 1H), 7.41 (dd, J = 8.3, 2.0 Hz, 1H), 7.32 (s, 4H), 7.17 (d, J = 1.9 Hz, 1H), 6.86 (d, J = 8.3 Hz, 1H), 6.61 (t, J = 73.6 Hz, 1H), 4.56 (s, 2H), 4.21 (q, J = 7.1 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H), 1.19−1.11 (m, 2H), 1.09− 1.00 (m, 2H). 13 [4,5]imidazo [1,2-a]pyrazin-7-yl)pyrido [2,3-d]pyrimidin-7(8H)-one (8). Light yellow solid; 30% yield.…”

“…This will further cause abnormalities in RNA splicing, gene expression, and genome stability, resulting in a phenomenon called synthetic death. 8 These findings encouraged the initiation of drug discovery work to target MAT2A for the treatment of MTAP-deficient cancers. 9 Analogs of methionine have been used as lead compounds to discover substrate-competitive inhibitors of MAT2A since the 1960s but failed to progress due to insufficient affinity and selectivity.…”

“…The deletion of MTAP gene can induce the accumulation of MTA in cells, and MTA can inhibit the activity of protein arginase methyltransferase 5 (PRMT5), leading to the increased resistance of cancer cells to the critical enzyme that synthesizes SAM. This will further cause abnormalities in RNA splicing, gene expression, and genome stability, resulting in a phenomenon called synthetic death . These findings encouraged the initiation of drug discovery work to target MAT2A for the treatment of MTAP-deficient cancers …”

Genomic landscape of metastatic breast cancer (MBC) patients with methylthioadenosine phosphorylase (MTAP) loss

“…In vivo models have shown that MAT2a knockdown reduced the growth and development of MTAP deficient tumor cells [19]. IDE397, a small molecule inhibitor of MAT2A, is under investigation as a part of a Phase 1 trial for advanced solid tumors with MTAP deletion [20].…”