Selective inhibition of nicotinamide adenine dinucleotide kinases by dinucleoside disulfide mimics of nicotinamide adenine dinucleotide analogues

Petrelli, Riccardo; Sham, Yuk Y.; Chen, Liqiang; Felczak, Krzysztof; Bennett, Eric M.; Wilson, Daniel J.; Aldrich, Courtney C.; Yu, José S.; Cappellacci, Loredana; Franchetti, Palmarisa; Grifantini, Mario; Mazzola, Francesca; Stefano, Michele Di; Magni, Giulio; Pankiewicz, Krzysztof W.

doi:10.1016/j.bmc.2009.06.013

Cited by 23 publications

(26 citation statements)

References 43 publications

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“…Although a few inhibitors of NADK have been described, they have lacked potency and have not advanced to preclinical or clinical evaluation (Petrelli et al, 2009). 6-AN, an inhibitor of G6PD, had demonstrated antitumor effects, but there was clear evidence of neurotoxicity in animals and also in patients.…”

Section: Discussionmentioning

confidence: 99%

Suppression of Cytosolic NADPH Pool by Thionicotinamide Increases Oxidative Stress and Synergizes with Chemotherapy

et al. 2015

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NAD 1 kinase (NADK) is the only known cytosolic enzyme that converts NAD 1 to NADP 1 , which is subsequently reduced to NADPH. The demand for NADPH in cancer cells is elevated as reducing equivalents are required for the high levels of nucleotide, protein, and fatty acid synthesis found in proliferating cells as well as for neutralizing high levels of reactive oxygen species (ROS). We determined whether inhibition of NADK activity is a valid anticancer strategy alone and in combination with chemotherapeutic drugs known to induce ROS. In vitro and in vivo inhibition of NADK with either small-hairpin RNA or thionicotinamide inhibited proliferation. Thionicotinamide enhanced the ROS produced by several chemotherapeutic drugs and produced synergistic cell kill. NADK inhibitors alone or in combination with drugs that increase ROS-mediated stress may represent an efficacious antitumor combination and should be explored further.

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Section: Discussionmentioning

confidence: 99%

Suppression of Cytosolic NADPH Pool by Thionicotinamide Increases Oxidative Stress and Synergizes with Chemotherapy

et al. 2015

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“…26 was a direct mimic of 24, while compound 25 was designed as an analogue of 21. Nucleophilic displacement of bromide in ethylbromoacetate (76) by tert-butylcarbazate (75) furnished (N1-tert-butoxycarbonyl-hydrazino)-acetic acid ethyl ester (77). The addition of succinic acid to a DMF solution of 77 at 75 °C for 18 h, gave the butyric acid derivative 78.…”

Section: Design Synthesis and Activity Of Nmant/ Namnat Inhibitorsmentioning

confidence: 99%

“…If cancer cells require higher levels of NADH than normal ones, inhibitors of human NAD kinase may show some anticancer effects. Thus, the design of potent inhibitors of human NAD kinase is of great interest as tools for biochemical studies of NAD biochemical pathways and as potential therapeutics in disorders related to oxidative stress and angiogenesis, including cancer [75].…”

Section: Potential Therapeutic Applications Of Nad Kinase Inhibitorsmentioning

confidence: 99%

NMN/NaMN Adenylyltransferase (NMNAT) and NAD Kinase (NADK) Inhibitors: Chemistry and Potential Therapeutic Applications

Petrelli

Felczak

Cappellacci

2011

CMC

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Nicotinamide adenine dinucleotide (NAD(+)) has a crucial role in many cellular processes, both as a coenzyme for redox reactions and as a substrate to donate ADP-ribose units. Thus, enzymes involved in NAD(+) metabolism are attractive targets for drug discovery against a variety of human diseases. Herein we focus on two of them: NMN/NaMN adenylyltransferase (NMNAT) and NAD kinase (NADK). NMNAT is a key enzyme in all organisms catalyzing coupling of ATP and NMN or NaMN yielding NAD or NaAD, respectively. NADKs are ubiquitous enzymes involved in the last step of the biosynthesis of NADP. They phosphorylate NAD to produce NADP using ATP (or inorganic polyphosphates) in the presence of Mg(2+). No other pathway of NADP biosynthesis has been found in prokaryotic or eukaryotic cells. In this review we provide a comprehensive summary of NMNAT and NADK inhibitors highlighting their chemical modifications by different synthetic approaches, and structure-activity relationships depending on their potential therapeutic applications.

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“…(9), inhibits LmNADK1 with K i = 20 M; apparently, the N sub-site of the NAD binding pocket of the Listeria enzyme is quite promiscuous and tolerates substitution of nicotinamide riboside by adenosine quite well. As such, we have found that DTA and its 8-bromo analogues inhibit human and mycobacterium NAD kinase (vide infra) [19].…”

Section: Modular Character and Variety Of Confor-mations Of Enzyme Bomentioning

confidence: 98%

Rehab of NAD(P)-Dependent Enzymes with NAD(P)-Based Inhibitors

Felczak

Pankiewicz

2011

CMC

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A large number of enzymes that use nicotinamide adenine dinucleotide NAD or its phosphorylated form NADP as a cofactor or substrate were found to play an important role in the growth and reproduction of living organisms. NAD(P)-dependent and NAD(P)-utilizing enzymes [NAD(P)-addicted?] have been extensively investigated and implicated in a wide variety of diseases. NAD, generally considered a key component involved in redox reactions, has been found to participate in a broad spectrum of cellular processes, including signal transduction, DNA repair, and post-translational protein modifications. The reduced form of NADP, i.e. NADPH, guards the cell against oxidative stress and it has been suggested that suppression of NADPH oxidase activity could result in anti-angiogenesis and anticancer effects. Consequently, small molecule NAD(P)-based inhibitors that selectively bind at the NAD(P)-binding domain of the targeted enzyme have been designed for novel treatment of medical disorders. The NAD(P)-binding domain is modular in nature; it can be divided into three sub-sites, the nicotinamide monophosphate (NMN) binding sub-site (N sub-site), the adenosine monophosphate (AMP) binding sub-site (A sub-site), and the pyrophosphate binding sub-site (P sub-site or P-groove). Each sub-site plays an important role in securing proper and tight binding; however, each has its own requirements. In this review we discuss a number of conformational and structural factors that might affect (improve) the affinity of various inhibitors to these sub-sites, as well as to the whole binding domain. We have focused on potential selectivity of NAD(P)-like molecules toward targeted enzymes and their potential application in biology and medicine.

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Selective inhibition of nicotinamide adenine dinucleotide kinases by dinucleoside disulfide mimics of nicotinamide adenine dinucleotide analogues

Cited by 23 publications

References 43 publications

Suppression of Cytosolic NADPH Pool by Thionicotinamide Increases Oxidative Stress and Synergizes with Chemotherapy

Suppression of Cytosolic NADPH Pool by Thionicotinamide Increases Oxidative Stress and Synergizes with Chemotherapy

NMN/NaMN Adenylyltransferase (NMNAT) and NAD Kinase (NADK) Inhibitors: Chemistry and Potential Therapeutic Applications

Rehab of NAD(P)-Dependent Enzymes with NAD(P)-Based Inhibitors

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