Discovery of Potent and Oral Bioavailable MAT2A Inhibitors for the Treatment of MTAP-Deleted Tumors

被引：3
|
作者：
Li, Qun [1 ]
Zang, Yang [1 ]
An, Dan [1 ]
Liu, Lifei [1 ]
Jiang, Wen [1 ]
Liu, Rongchen [1 ]
Su, Jiangtao [2 ]
Yang, Jun [1 ,3 ,4 ]
Li, Lie [1 ]
Zhang, Xuejun [1 ]
机构：
[1] Hubei Biopharmaceut Ind Technol Inst Inc, Wuhan 430075, Hubei, Peoples R China
[2] Hubei Univ Technol, Wuhan 430068, Peoples R China
[3] Humanwell Healthcare Grp Co Ltd, Wuhan 430075, Hubei, Peoples R China
[4] Humanwell Pharmaceut US Inc, Ballwin, MO 63011 USA
来源：
ACS MEDICINAL CHEMISTRY LETTERS | 2023年 / 14卷 / 12期
关键词：
Allosteric Inhibitor; Methionine Adenosyltransferase2A (MAT2A); Methylthioadenosine Phosphorylase (MTAP); 5'-Methylthioadenosine (MTA); 3H-Pyrido[1,2-c]pyrimidin-3-one; METHYLTRANSFERASE; METHIONINE;
D O I：
10.1021/acsmedchemlett.3c00488
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
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.
引用
收藏
页码：1876 / 1881
页数：6
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