化学
烟酰胺
体内
广告
生物化学
药理学
体外
酶
生物
生物技术
作者
Robert D. Barrows,Daniel E. Jeffries,Mahesh Vishe,Hanna Tukachinsky,Shao‐Liang Zheng,Fanfan Li,Zhenjie Ma,Xiaolei Li,Sun Jin,Haobin Song,Ruonan Zhang,Shaofeng Zhang,Jing Ni,Haofei Luan,Wen Li,Yan Rongshan,Ying Chen,Matthew D. Shair
标识
DOI:10.1021/acs.jmedchem.2c01166
摘要
NNMT uses SAM as a cofactor to catalyze the methylation of nicotinamide, producing 1-methylnicotinamide. Recent studies have shown that NNMT upregulation in cancer-associated fibroblasts (CAFs) is required to maintain the CAF phenotype in high-grade serous carcinoma. These observations suggest that NNMT should be evaluated as a therapeutic target, especially in cancer. Although several small-molecule inhibitors of NNMT have been identified, there remains a need for highly potent and selective inhibitors with excellent in vivo activity and ADME properties that can be used as reliable chemical probes. We have identified azaindoline carboxamide 38 as a selective and potent NNMT inhibitor with favorable PK/PD and safety profiles as well as excellent oral bioavailability and pharmaceutical properties. Our mechanistic studies indicate that 38 binds uncompetitively with SAM but competitively with nicotinamide consistent with its binding in the nicotinamide binding site and likely forming a positive interaction with SAM.
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