Discovery of Potent and Oral Bioavailable MAT2A Inhibitors for the Treatment of MTAP-Deleted Tumors,ACS Medicinal Chemistry Letters

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Discovery of Potent and Oral Bioavailable MAT2A Inhibitors for the Treatment of MTAP-Deleted Tumors
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2023-12-04 , DOI: 10.1021/acsmedchemlett.3c00488
Qun Li _{1,

2} , Yang Zang _{1,

2} , Dan An _{1,

2} , Lifei Liu _{1,

2} , Wen Jiang _{1,

2} , Rongchen Liu _{1,

2} , Jiangtao Su ₃ , Jun Yang _{1,

2,

4} , Lie Li _{1,

2} , Xuejun Zhang _{1,

2}

Affiliation

Inhibition of methionine adenosyltransferase 2A (MAT2A) has received significant interest because of its implication as a synthetic lethal target in methylthioadenosine phosphorylase (MTAP)-deleted cancers. Here, we report the discovery of a series of 3H-pyrido[1,2-c]pyrimidin-3-one derivatives as novel MAT2A inhibitors. The selected compound 30 exhibited high potency for MAT2A inhibition and a favorable pharmacokinetic profile. Furthermore, in an HCT-116 MTAP-deleted xenograft model, compound 30 showed better in vivo potency than current clinical compound AG-270.

中文翻译：

发现用于治疗 MTAP 缺失肿瘤的有效口服生物利用度 MAT2A 抑制剂

甲硫氨酸腺苷转移酶 2A (MAT2A) 的抑制因其作为甲硫腺苷磷酸化酶 (MTAP) 缺失癌症中的合成致死靶点而受到广泛关注。在这里，我们报告了一系列 3 H -pyrido[1,2- c ]pyrimidin-3-one 衍生物作为新型 MAT2A 抑制剂的发现。所选化合物30对 MAT2A 抑制表现出高效力和良好的药代动力学特征。此外，在 HCT-116 MTAP 缺失的异种移植模型中，化合物30显示出比目前临床化合物AG-270更好的体内效力。

更新日期：2023-12-04

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