Novel nicotinamide analog as inhibitor of nicotinamide N-methyltransferase

Ruf, Sven; Hallur, Mahanandeesha Siddappa; Anchan, Nisha K.; Swamy, Indu N.; Murugesan, Karthikai Raj; Sarkar, Sayantani; Narasimhulu, Lokesh Kananti; Putta, V. P. Rama Kishore; Shaik, Shama; Chandrasekar, Devaraj Venkatapura; Mane, Vishal Subhash; Kadnur, Sanjay V.; Joghee, Suresh; Bhamidipati, Ravi Kanth; Singh, Manvi; Burri, Raghunadha Reddy; Kristam, Rajendra; Schreuder, Herman; Czech, Jörg; Rudolph, Christine; Marker, Alexander; Langer, Thomas; Mullangi, Ramesh; Yura, Takeshi; Gosu, Ramachandraiah; Kannt, Aimo; Dhakshinamoorthy, Saravanakumar; Rajagopal, Sridharan

doi:10.1016/j.bmcl.2018.01.058

Cited by 31 publications

(30 citation statements)

References 19 publications

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“…In addition, we also synthesized two recently described NNMT inhibitors, compound 2 and 6-(methylamino)-nicotinamide, following the procedures described in the corresponding publications. 21,31 The structures of these reference compounds are provided in Figure 2.…”

Section: Resultsmentioning

confidence: 99%

Bisubstrate Inhibitors of Nicotinamide N-Methyltransferase (NNMT) with Enhanced Activity

Gao

Haren

Moret³

et al. 2019

J. Med. Chem.

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Nicotinamide N -methyltransferase (NNMT) catalyzes the methylation of nicotinamide to form N -methylnicotinamide. Overexpression of NNMT is associated with a variety of diseases, including a number of cancers and metabolic disorders, suggesting a role for NNMT as a potential therapeutic target. By structural modification of a lead NNMT inhibitor previously developed in our group, we prepared a diverse library of inhibitors to probe the different regions of the enzyme’s active site. This investigation revealed that incorporation of a naphthalene moiety, intended to bind the hydrophobic nicotinamide binding pocket via π–π stacking interactions, significantly increases the activity of bisubstrate-like NNMT inhibitors (half-maximal inhibitory concentration 1.41 μM). These findings are further supported by isothermal titration calorimetry binding assays as well as modeling studies. The most active NNMT inhibitor identified in the present study demonstrated a dose-dependent inhibitory effect on the cell proliferation of the HSC-2 human oral cancer cell line.

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Section: Resultsmentioning

confidence: 99%

Bisubstrate Inhibitors of Nicotinamide N-Methyltransferase (NNMT) with Enhanced Activity

Gao

Haren

Moret³

et al. 2019

J. Med. Chem.

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“…The compound is part of a series of related molecules. The structure-activity relationship within the series have been described elsewhere 14 .…”

Section: Resultsmentioning

confidence: 99%

A small molecule inhibitor of Nicotinamide N-methyltransferase for the treatment of metabolic disorders

Kannt

Rajagopal

Kadnur

et al. 2018

Sci Rep

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101

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Nicotinamide N-methyltransferase (NNMT) is a cytosolic enzyme that catalyzes the transfer of a methyl group from the co-factor S-adenosyl-L-methionine (SAM) onto the substrate, nicotinamide (NA) to form 1-methyl-nicotinamide (MNA). Higher NNMT expression and MNA concentrations have been associated with obesity and type-2 diabetes. Here we report a small molecule analog of NA, JBSNF-000088, that inhibits NNMT activity, reduces MNA levels and drives insulin sensitization, glucose modulation and body weight reduction in animal models of metabolic disease. In mice with high fat diet (HFD)-induced obesity, JBSNF-000088 treatment caused a reduction in body weight, improved insulin sensitivity and normalized glucose tolerance to the level of lean control mice. These effects were not seen in NNMT knockout mice on HFD, confirming specificity of JBSNF-000088. The compound also improved glucose handling in ob/ob and db/db mice albeit to a lesser extent and in the absence of weight loss. Co-crystal structure analysis revealed the presence of the N-methylated product of JBSNF-000088 bound to the NNMT protein. The N-methylated product was also detected in the plasma of mice treated with JBSNF-000088. Hence, JBSNF-000088 may act as a slow-turnover substrate analog, driving the observed metabolic benefits.

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“…1-MNA is known to inhibit NNMT through enzymatic reaction product inhibition (10), but 1-MNA itself has been shown to play a unique role in tumor proliferation and drug resistance (5,6). A growing number of inhibitors have recently been reported including chloroacetamide-based covalent NNMT inhibitors, nicotinamide analogues, quinolone (inhibitors based on NNMT's alternative substrate), sinefungin (general methyltransferase inhibitor), and bisubstrate-like inhibitors (25)(26)(27)(28)(29)(30)(31). All reported inhibitors are chemosynthetic, and more research is required to certify their potential side effects.…”

Section: Discussionmentioning

confidence: 99%

Vanillin downregulates NNMT and attenuates NNMT‑related resistance to 5‑fluorouracil via ROS‑induced cell apoptosis in colorectal cancer cells

Kong

Tong

et al. 2021

Oncol Rep

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Chemoresistance is the main cause of poor prognosis in colorectal cancer (CRC). Nicotinamide N-methyltransferase (NNMT) is a metabolic enzyme that is upregulated in various tumor types. It has been reported that NNMT inhibits apoptosis and enhances resistance to 5-fluorouracil (5-Fu) via inhibition of the apoptosis signal regulating kinase 1 (ASK1)-p38 MAPK pathway in CRC cells. A natural product library was screened, and it was found that vanillin, also known as 4-hydroxy-3-methoxybenzaldehyde, a plant secondary metabolite found in several essential plant oils, mainly Vanilla planifolia, Vanilla tahitensis, and Vanilla pompon, may be a promising anticancer compound targeted to NNMT. The aim of the present study was to explore the effect of vanillin on promoting apoptosis and attenuating NNMT-induced resistance to 5-Fu in CRC. Lentiviral vectors of short hairpin RNA and small interfering RNA were transfected into HT-29 cells to construct NNMT-knockdown HT-29 cell lines. Vectors containing an open reading frame of NNMT were stably transfected into SW480 cells to induce NNMT overexpression in SW480 cell lines. Vanillin was found to inhibit the mRNA and protein expression levels of NNMT following the inhibition of NNMT activity in HT-29 cell lines. Vanillin was able to reverse NNMT-induced increased cell proliferation, decreased cell apoptosis and resistance to 5-Fu by inhibiting NNMT expression. Furthermore, it increased cell apoptosis by activating the ASK1-p38 MAPK pathway, which could be inhibited by NNMT. In addition, vanillin increased cell apoptosis by promoting mitochondrial damage and reactive oxygen species. In vivo, the combination of vanillin with 5-Fu yielded a notable synergy in inhibiting tumor growth and inducing apoptosis. Considering that vanillin is an important flavor and aromatic component used in foods worldwide, vanillin is deemed to be a promising anticancer candidate by inhibiting NNMT and may attenuate NNMT-induced resistance to 5-Fu in human CRC therapy with few side effects.

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Novel nicotinamide analog as inhibitor of nicotinamide N-methyltransferase

Cited by 31 publications

References 19 publications

Bisubstrate Inhibitors of Nicotinamide N-Methyltransferase (NNMT) with Enhanced Activity

Bisubstrate Inhibitors of Nicotinamide N-Methyltransferase (NNMT) with Enhanced Activity

A small molecule inhibitor of Nicotinamide N-methyltransferase for the treatment of metabolic disorders

Vanillin downregulates NNMT and attenuates NNMT‑related resistance to 5‑fluorouracil via ROS‑induced cell apoptosis in colorectal cancer cells

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