Abstract 3757: Development of potent orally bioavailable inhibitors of nicotinamide N-methyl transferase

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Abstract Nicotinamide N-methyltransferase (NNMT) has emerged as a cancer therapeutic target as a master metabolic regulator that catalyzes the differentiation of normal fibroblasts to cancer associated fibroblasts (CAFs) in the stromal tissue surrounding various tumors, most notably ovarian carcinomas. NNMT activity depletes S-adenosyl methionine (SAM) reducing histone methylation. This change in the stromal epigenome results in changes to the interstitial tumor space which in turn promotes tumor growth and metastasis We will present the development of novel orally bioavailable selective inhibitors of NNMT. We conducted a high throughput screen (HTS) of over 150, 000 compounds against NNMT, using MTase-Glo™ (Methyltransferase Glo™, Promega), to identify actionable chemical matter for medicinal chemistry. In collaboration with NCI’s Chemical Biology Consortium (CBC), we carried out a structure-based drug discovery campaign with a triazole hit which emerged from the high-throughput screen. To support compound optimization, we developed multiple orthogonal assays, including biochemical methyltransferase counter-assays to assess compound activity and selectivity, a CRISPR-based HiBiT tagged NNMT cell line for CETSA-based cell engagement assays and a cellular functional mass spectrometry-based assay that measures the production of the NNMT enzymatic product 1-methylnicotinamide (1-MNA). Our medicinal chemistry optimization campaign led to the development of inhibitors with low nanomolar cellular potency, oral bioavailability and dose-dependent inhiibtion of NNMT in mice. The lead compound ‘960 is the most potent inhibitor of human NNMT disclosed to date but its potency against mouse NNMT is right shifted (hNNMT IC50 12 nM, mNNMT IC50 240 nM). In MC38 tumor bearing mice, topical treatment with ‘960 significantly reduced tumor growth compared to vehicle. The less active enantiomer ‘961 (hNNMT IC50 1.36 μM, mNNMT IC50 21.5 μM) serves as a chemical negative control in most of our studies. In an EO771-LMB tumor model, ‘960 pre-treatment before IV injection of cancer cells significantly reduced lung metastasis burden. Current efforts are ongoing to generate mice with human NNMT to establish the accurate dose for efficacy in cancer mouse models. Citation Format: Samarjit Patnaik, Janna Heide, Ke Kong, Mark Eckert, Maria Allega, Min Shen, Hongmao Sun, Jonathan Shrimp, Quinlin Hanson, Ken Cheng, Andrew Flint, William J. Moore, Matthew Hall, Gordon M. Stott, Ernst Lengyel. Development of potent orally bioavailable inhibitors of nicotinamide N-methyl transferase [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3757.

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