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

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

  • J Med Chem. 2022 Nov 10;65(21):14642-14654. doi: 10.1021/acs.jmedchem.2c01166.
Robert D Barrows 1 Daniel E Jeffries 1 Mahesh Vishe 1 Hanna Tukachinsky 1 Shao-Liang Zheng 1 Fanfan Li 2 Zhenjie Ma 2 Xiaolei Li 2 Shujuan Jin 2 Haobin Song 2 Ruonan Zhang 2 Shaofeng Zhang 2 Jing Ni 2 Haofei Luan 2 Lei Wen 2 Yan Rongshan 3 Chen Ying 3 Matthew D Shair 1
Affiliations

Affiliations

  • 1 Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, United States.
  • 2 Pharmaron Beijing Co., Ltd., 6 Taihe Road, BDA, Beijing 100176, China.
  • 3 WuXi AppTec Co., Ltd., #288 FuTe ZhongLu WaiGaoQiao Free Trade Zone, Shanghai 200131, China.
Abstract

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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-151813
    99.35%, NNMT Inhibitor