Potent Uncompetitive Inhibitors of Nicotinamide N -Methyltransferase (NNMT) as In Vivo Chemical Probes.

Autor:	Barrows RD; Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, United States., Jeffries DE; Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, United States., Vishe M; Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, United States., Tukachinsky H; Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, United States., Zheng SL; Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, United States., Li F; Pharmaron Beijing Co., Ltd., 6 Taihe Road, BDA, Beijing 100176, China., Ma Z; Pharmaron Beijing Co., Ltd., 6 Taihe Road, BDA, Beijing 100176, China., Li X; Pharmaron Beijing Co., Ltd., 6 Taihe Road, BDA, Beijing 100176, China., Jin S; Pharmaron Beijing Co., Ltd., 6 Taihe Road, BDA, Beijing 100176, China., Song H; Pharmaron Beijing Co., Ltd., 6 Taihe Road, BDA, Beijing 100176, China., Zhang R; Pharmaron Beijing Co., Ltd., 6 Taihe Road, BDA, Beijing 100176, China., Zhang S; Pharmaron Beijing Co., Ltd., 6 Taihe Road, BDA, Beijing 100176, China., Ni J; Pharmaron Beijing Co., Ltd., 6 Taihe Road, BDA, Beijing 100176, China., Luan H; Pharmaron Beijing Co., Ltd., 6 Taihe Road, BDA, Beijing 100176, China., Wen L; Pharmaron Beijing Co., Ltd., 6 Taihe Road, BDA, Beijing 100176, China., Rongshan Y; WuXi AppTec Co., Ltd., #288 FuTe ZhongLu WaiGaoQiao Free Trade Zone, Shanghai 200131, China., Ying C; WuXi AppTec Co., Ltd., #288 FuTe ZhongLu WaiGaoQiao Free Trade Zone, Shanghai 200131, China., Shair MD; Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2022 Nov 10; Vol. 65 (21), pp. 14642-14654. Date of Electronic Publication: 2022 Oct 26.
DOI:	10.1021/acs.jmedchem.2c01166
Abstrakt:	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.
Databáze:	MEDLINE
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