Methionine adenosyltransferase 2A (MAT2A) has emerged as a synthetic lethal target in methylthioadenosine phosphorylase (MTAP)-deleted cancers, which account for approximately 15% of human tumors and currently lack effective therapies. However, existing MAT2A inhibitors often suffer from limited potency, suboptimal selectivity, and undesirable toxicity. Herein, we report a series of tricyclic furo[2,3-f]quinazolin-7(6H)-one derivatives as MAT2A inhibitors based on structure-based drug design. Among them, compound 18 (ZS34) exhibited potent MAT2A inhibitory activity (IC₅₀ = 13.7 nM) and selectively suppressed the growth of MTAP-deficient cancer cells. Furthermore, 18 demonstrated on-target engagement in MTAP-deficient cells, as evidenced by inhibition of SAM synthesis, reduction of SDMA levels, and induction of DNA damage. Additionally, 18 displayed minimal hERG and UGT1A1 liabilities along with favorable oral pharmacokinetics. In the HCT116 MTAP^-/- xenograft mouse model, the oral administration of 18 demonstrated significant antitumor efficacy without obvious toxicity. These results support 18 as a promising candidate for targeting MTAP-deficient cancers.

2025-11-01·Journal of Thoracic Oncology

Clinical Significance of MTAP Deletions and their Overlap with Concurrent Oncogenic Driver Alterations Including EGFR in Non-Small Cell Lung Cancer

Article

作者: Eckert, Scott ; Ladanyi, Marc ; Riely, Gregory J ; Choudhury, Noura J ; Bodd, Francis M ; Arbour, Kathryn C ; Muldoon, Daniel ; Yang, Soo-Ryum ; Kris, Mark G ; Harada, Guillherme ; Thummalapalli, Rohit ; Ross, Jessica S ; Offin, Michael ; Awad, Mark M ; Febres-Aldana, Christopher A ; Jeng, Mark Y ; Pupo, Amanda ; Yu, Helena ; Berger, Michael ; Drilon, Alexander ; Falcon, Christina ; Sauter, Jennifer L ; Bandlamudi, Chaitanya

INTRODUCTION:

MTAP (methylthioadenosine phosphorylase) deletions (dels) occur with CDKN2A deletions in a subset of non-small cell lung cancers (NSCLCs). These deletions have been associated with inferior survival in several tumor types, and they may be targetable by PRMT5 and MAT2A inhibitors via synthetic lethality. Their co-occurrence with oncogenic drivers including EGFR is underexplored.

METHODS:

We analyzed 4,926 NSCLC tumors sequenced with MSK-IMPACT, a next-generation sequencing panel, and examined the incidence of MTAP dels with a copy number-based approach.

RESULTS:

475 of 4,926 NSCLC tumors (10%) harbored an MTAP del. Among 258 stage IV MTAP-del NSCLC tumors, 214 (83%) also had a co-occurring oncogenic driver alteration, including 123 (48%) with EGFR mutations. Baseline MTAP deletion was associated with shorter time to osimertinib monotherapy discontinuation (19.0 vs 24.9 months, HR 1.8, CI 1.02 - 3.15, P=0.01), but did not statistically significantly affect overall survival (38.4 vs 40.5 months, HR 1.7, CI 0.8 - 3.6, P=0.1). In patients who developed resistance to osimertinib with paired pre- and post-treatment tissue samples, acquired MTAP del was identified in 9/69 patients (13%). A heavily pretreated patient with metastatic EGFR-mutant, MTAP-del NSCLC had a confirmed partial response to treatment with PRMT5 inhibitor monotherapy (BMS-986504).

CONCLUSIONS:

MTAP dels frequently co-occur with oncogenic driver alterations and can develop at time of osimertinib resistance. A patient with oncogenic driver-positive, MTAP-del NSCLC had a partial response to PRMT5 inhibitor treatment. This work could inform future trials of PRMT5 and MAT2A inhibitors.

2025-04-10·ACS Medicinal Chemistry Letters

Structure-Based Discovery of a Series of Novel MAT2a Inhibitors

Article

作者: Zhang, Junjie ; Wang, Yingqing ; Huan, Xiajuan ; Ren, Ruyue ; Liu, Tongchao ; Yang, Peng ; Xiong, Bing ; Wang, Li ; Zhou, Yushan ; Miao, Ze-Hong

Methionine adenosyltransferase 2a (MAT2a) has emerged as a promising therapeutic target due to its role in the synthetic lethality mechanism associated with MTAP-deficient tumors. In this study, we describe our efforts to identify a novel series of MAT2a inhibitors through a fragment-based joining strategy, leading to the development of a single molecule that occupies the allosteric site of the MAT2a dimer. 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.

100 项与 Mat2A inhibitors(Shenyang Pharmaceutical University) 相关的药物交易

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