Overview of Methionine Adenosyltransferase 2A (MAT2A) as an Anticancer Target: Structure, Function, and Inhibitors

Abstract

Methionine adenosyltransferase 2A (MAT2A) is a rate-limiting enzyme in the methionine cycle that primarily catalyzes the synthesis of S-adenosylmethionine (SAM) from methionine and adenosine triphosphate (ATP). MAT2A has been recognized as a therapeutic target for the treatment of cancers. Recently, a few MAT2A inhibitors have been reported, and three entered clinical trials to treat solid tumorsor lymphoma with MTAP loss. This review aims to summarize the current understanding of the roles of MAT2A in cancer and the discovery of MAT2A inhibitors. Furthermore, a perspective on the use of MAT2A inhibitors for the treatment of cancer is also discussed. We hope to provide guidance for future drug design and optimization via analysis of the binding modes of known MAT2A inhibitors.

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

“…Similar to AG-270 and AGI-43192, 8 was capable of forming a hydrogenbonding interaction with Arg313 and π−π stacking interaction with Phe18, which was considered to be the key to binding with MAT2A. 9 Apart from that, the basic tricyclic rings might interact favorably with the acidic side chain of D191 residue, as they were adjacent in the docking pose. Additionally, the docking result indicated favorable interactions between the C− F bond and carbonyl group and the electropositive carbon of the carbonyl group of Gly273 and Gly275, suggesting the formation of halogen−carbonyl interactions.…”

“…Transposing the methylamino position of the tricyclic fragment resulted in a compound (10, MAT2A IC 50 = 20 nM) that displayed similar activities to 8. Interestingly, changing the direction that the piperazine conjugated with the indazole led to a compound (9) with >60 lower in vitro potency than 8. We also discovered that replacing the piperazine of 10 with piperazin-2-one resulted in a slight increase in the IC 50 of proliferation inhibition.…”

“…1 H NMR (600 MHz, chloroform-d) δ 8.78 (s, 1H), 7.94 (d, J = 7.2 Hz, 2H), 7.75 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 8.3 Hz, 1H), 7.32 (d, J = 3.5 Hz, 4H), 6.60 (t, J = 73.5 Hz, 1H), 4.17 (dd, J = 39.1, 6.3 Hz, 4H), 3.90 (s, 2H), 2.97 (t, J = 5.6 Hz, 2H), 2.56 (s, 3H), 1.29 (t, J = 7.3 Hz, 3H). 13 [4,5]imidazo [1,2-a]pyrazin-8-yl)pyrido [2,3-d]pyrimidin-7(8H)-one (9). Light yellow solid; 17% yield.…”

“…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. 10 It was not until 2017 that Pfizer researchers identified the first allosteric MAT2A inhibitor, PF-9366, which inhibited cellular SAM synthesis with submicromolar potency.…”

“…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 …”