AG-270 showed lack of cancer specificity in combination with rMETase when tested on both cancer and normal cells. The present results contrast with numerous chemotherapy agents, which in combination with rMETase are synergistic on cancer cells but not on normal cells. The present findings suggest that MAT2A inhibition affects crucial metabolic pathways in normal as well as cancer cell types and thus AG-270 may not be suitable as a cancer-specific therapeutic strategy.

This study developed two novel MAT2A-targeted PET tracers: the 18F-labeled [18F]1d, derived from AZ-28, demonstrates rapid tumor uptake (equilibrium ∼20 min), high tumor-to-muscle ratio, and specific MAT2A binding in H1975 xenografts, though it shows some bone uptake due to defluorination; the 68Ga-labeled [68Ga]1s, based on AG-270, retains high MAT2A affinity (IC50 = 6.23 nM) and exhibits superior pharmacokinetics─low liver uptake, renal clearance, and high cellular internalization (80%)...Molecular docking confirms key interactions with the MAT2A allosteric site. Both tracers provide promising tools for solid tumor diagnosis, treatment monitoring, and precision oncology.

MTA-cooperative PRMT5 inhibitors such as BMS-986504/MRTX1719 and AMG 193 target the PRMT5-MTA complex, while inhibitors of the SAM synthetase methionine adenosyl transferase 2A (MAT2A), such as IDE397, deprive PRMT5 of its methyl donor SAM. In this review article, we summarize the mechanisms of action, preclinical data, and clinical data available thus far for these novel classes of oncology precision medicine and discuss potential future directions relevant to MTAP deletion as a promising synthetic lethal vulnerability for cancer therapy.

P1/2, N=308, Recruiting, Servier Bio-Innovation LLC | Phase classification: P1 --> P1/2 | N=27 --> 308 | Trial completion date: May 2026 --> Oct 2031 | Trial primary completion date: May 2026 --> Oct 2031

P1, N=140, Recruiting, BeiGene | Trial completion date: Dec 2026 --> Dec 2028

P1, N=186, Recruiting, Guangdong Provincial People's Hospital(Guangdong Academy of Medical Sciences); Guangdong Provincial People's Hospital(Guangdong Academy of Medical Sci

Guided by the costructure of AZ-28 in complex with the MAT2a dimer, compound 9 was synthesized, demonstrating potent MAT2a inhibition (IC50 = 20 nM) and significantly enhanced antiproliferative activity (IC50 = 10 nM against HAP1MTAP-/- cells). Moreover, compound 9 exhibited improved selectivity compared to both AZ-28 and AG-270.

P1, N=186, Recruiting, CSPC ZhongQi Pharmaceutical Technology Co., Ltd. | Not yet recruiting --> Recruiting

Compound 28 also showed favorable pharmacokinetic properties and the improved in vivo anticancer activity in MTAP-deficient tumor models. These findings suggest new directions for the discovery and development of highly selective MAT2A inhibitors.

Both of these lead compounds demonstrate increased plasma drug exposure and exhibit significant efficacy in xenograft models that are depleted of MTAP. We hope that identifying a brain-penetrant MAT2A inhibitor will create new opportunities to explore the potential therapeutic effects of S-adenosylmethionine modulation in the central nervous system.

P1, N=80, Recruiting, InSilico Medicine Hong Kong Limited | Not yet recruiting --> Recruiting

Different from AG-270, SCR-7952 exhibited little influence on metabolic enzymes and did not increase the plasma levels of bilirubin. The mechanism was via the aggravated inhibition of PRMT5 and FANCA splicing perturbations. These results indicated that SCR-7952 could be a potential therapeutic candidate for the treatment of MTAP-deleted cancers, both monotherapy and in combination with PRMT5 inhibitors.