Novel Inhibitors of Nicotinamide-N-Methyltransferase for the Treatment of Metabolic Disorders

Kannt, Aimo; Rajagopal, Sridharan; Hallur, Mahanandeesha Siddappa; Swamy, Indu N.; Kristam, Rajendra; Dhakshinamoorthy, Saravanakumar; Czech, Jörg; Zech, Gernot; Schreuder, Herman; Ruf, Sven

doi:10.3390/molecules26040991

Cited by 17 publications

(19 citation statements)

References 29 publications

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“…The key to unlocking this understanding was the first publication of the crystal structure of NNMT co-crystalised with nicotinamide and SAH by Peng and colleagues [200]. The majority of the first small-molecule inhibitors developed were focussed upon targeting NNMT in obesity and alcohol-related fatty liver disease [201][202][203][204][205]. Many of these inhibitors have yet to be tested in in vitro cancer models systems, and questions remain about their selectivity towards NNMT in relation to other methyltransferases as well as their cell permeability.…”

Section: Small-molecule Inhibitors Of Nnmt Activitymentioning

confidence: 99%

Nicotinamide N-Methyltransferase: An Emerging Protagonist in Cancer Macro(r)evolution

Parsons

Facey

2021

Biomolecules

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Nicotinamide N-methyltransferase (NNMT) has progressed from being considered merely a Phase II metabolic enzyme to one with a central role in cell function and energy metabolism. Over the last three decades, a significant body of evidence has accumulated which clearly demonstrates a central role for NNMT in cancer survival, metastasis, and drug resistance. In this review, we discuss the evidence supporting a role for NNMT in the progression of the cancer phenotype and how it achieves this by driving the activity of pro-oncogenic NAD+-consuming enzymes. We also describe how increased NNMT activity supports the Warburg effect and how it promotes oncogenic changes in gene expression. We discuss the regulation of NNMT activity in cancer cells by both post-translational modification of the enzyme and transcription factor binding to the NNMT gene, and describe for the first time three long non-coding RNAs which may play a role in the regulation of NNMT transcription. We complete the review by discussing the development of novel anti-cancer therapeutics which target NNMT and provide insight into how NNMT-based therapies may be best employed clinically.

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Section: Small-molecule Inhibitors Of Nnmt Activitymentioning

confidence: 99%

Nicotinamide N-Methyltransferase: An Emerging Protagonist in Cancer Macro(r)evolution

Parsons

Facey

2021

Biomolecules

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“…Several NNMT inhibitors, which are expected to be useful for the treatment of metabolic disorders, have been developed and are available commercially. 16 Our findings suggest that NNMT inhibitors may be effective for the treatment of EC. Moreover, a new biosensor was recently developed for rapid quantification of 1-MNA, which is a metabolite produced by NNMT.…”

Section: Discussionmentioning

confidence: 68%

Nicotinamide N‐methyltransferase is related to MELF pattern invasion in endometrioid carcinoma

et al. 2021

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Grade 1 (G1) endometrioid carcinoma (EC) is relatively a good prognosis. However, in a minority of cases, G1 shows an aggressive histological pattern known as the microcystic, elongated, and fragmented (MELF) pattern. We previously reported that EC with high expression levels of S100A4 and serum deprivation‐response protein (SDPR) was related to MELF pattern invasion. However, the molecular features of the invasive front area of the MELF pattern have not been investigated. In this study, we searched for genes preferentially expressed in the invasive front area of EC with the MELF pattern using laser microdissection and RNA sequencing, and showed that nicotinamide N‐methyltransferase (NNMT) is related to MELF pattern invasiveness. Immunohistochemical analyses confirmed high NNMT expression in the invasive front area of the MELF pattern. Moreover, NNMT promoted migration, invasion, colony formation, epithelial–mesenchymal transition (EMT), and chemoresistance using EC cell lines. We speculate that depletion of NNMT promotes histone methylation and leads to tumor suppression because NNMT consumes S‐adenosyl methionine (SAM), which is an essential methylation cofactor. NNMT knockout cells showed enhanced expression of H3K9me2. RNA sequencing using NNMT knockout cell lines suggested that methylation of H3K9 leads to repression of the transcription of various oncogenic genes. Our findings demonstrate the possibility that NNMT inhibitors, which are expected to be used for the treatment of metabolic disorders, would be effective for the treatment of aggressive EC. This is the first report of gene analyses focusing on the morphological changes associated with MELF pattern invasion of EC.

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“…Subsequent studies clearly demonstrated NNMT involvement in fundamental events featuring tumorigenesis, namely, cell proliferation, migration and invasiveness (Figure 2), thus attributing to the enzyme a promising role as a molecular target for effective treatment of these tumors. NNMT 3D structure resolution [11], together with the identification of related kinetic mechanism-of-action [12], have triggered the design, synthesis and validation of a wide range of molecules that seem to act as potent inhibitors of enzyme activity [16][17][18][19][20][21][22][23][24][25][26][27], that could be used as novel anti-cancer therapeutics. Nicotinamide N-methyltransferae (NNMT) involvement in urological tumors.…”

Section: Discussionmentioning

confidence: 99%

“…Although the enzyme is described to be involved in the biotransformation and detoxification of many xenobiotics [1][2][3], porcine liver NNMT was only described to be active towards pyridine derivatives, such as quinoline, isoquinoline, and 1,2,3,4-tetrahydroisoquinoline, in addition to structural NA analogs, such as thionicotinamide and 3-acetylpyridine [10]. The resolution of tridimensional (3D) structures of purified human recombinant NNMT, together with the detection of the main amino acid residues involved in the catalysis [11], led to the discovery of the kinetic mechanism of NNMT [12], the identification of alternate enzyme substrates [13][14][15], as well as the design and assay of a great number of inhibitors [16][17][18][19][20][21][22][23][24][25][26][27].…”

Section: Introductionmentioning

confidence: 99%

The Utility of Nicotinamide N-Methyltransferase as a Potential Biomarker to Predict the Oncological Outcomes for Urological Cancers: An Update

et al. 2021

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Nicotinamide N-methyltransferase (NNMT) catalyzes the N-methylation reaction of nicotinamide, using S-adenosyl-L-methionine as the methyl donor. Enzyme overexpression has been described in many non-neoplastic diseases, as well as in a wide range of solid malignancies. This review aims to report and discuss evidence available in scientific literature, dealing with NNMT expression and the potential involvement in main urologic neoplasms, namely, renal, bladder and prostate cancers. Data illustrated in the cited studies clearly demonstrated NNMT upregulation (pathological vs. normal tissue) in association with these aforementioned tumors. In addition to this, enzyme levels were also found to correlate with key prognostic parameters and patient survival. Interestingly, NNMT overexpression also emerged in peripheral body fluids, such as blood and urine, thus leading to candidate the enzyme as promising biomarker for the early and non-invasive detection of these cancers. Examined results undoubtedly showed NNMT as having the capacity to promote cell proliferation, migration and invasiveness, as well as its potential participation in fundamental events highlighting cancer progression, metastasis and resistance to chemo- and radiotherapy. In the light of this evidence, it is reasonable to attribute to NNMT a promising role as a potential biomarker for the diagnosis and prognosis of urologic neoplasms, as well as a molecular target for effective anti-cancer treatment.

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Novel Inhibitors of Nicotinamide-N-Methyltransferase for the Treatment of Metabolic Disorders

Cited by 17 publications

References 29 publications

Nicotinamide N-Methyltransferase: An Emerging Protagonist in Cancer Macro(r)evolution

Nicotinamide N-Methyltransferase: An Emerging Protagonist in Cancer Macro(r)evolution

Nicotinamide N‐methyltransferase is related to MELF pattern invasion in endometrioid carcinoma

The Utility of Nicotinamide N-Methyltransferase as a Potential Biomarker to Predict the Oncological Outcomes for Urological Cancers: An Update

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