Anticancer agent CHS-828 inhibits cellular synthesis of NAD

Olesen, Uffe H.; Christensen, Mette K.; Björkling, Fredrik; Jäättelä, Marja; Jensen, Peter Buhl; Sehested, Maxwell; Nielsen, Søren

doi:10.1016/j.bbrc.2008.01.019

Cited by 114 publications

(117 citation statements)

References 27 publications

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“…At present there are 2 drugs in early clinical testing with NAD depletion by inhibition of Nampt as their principle mechanism of action, CHS 828/GMX1777 and FK866 [6,18]. A total of 104 patients, including those in the phase I clinical trial presented here, have been exposed to these drugs as reported in literature.…”

Section: Discussionmentioning

confidence: 99%

“…NAD is an important co-factor in the oxidative phosphorylation chain as well as a substrate for enzymes involved in genomic stability, apoptosis, cell signalling, stress tolerance and metabolism [5][6][7]. NAD depletion will lead to, eg lowered ATP levels and inhibition of poly(ADP-ribose) polymerases (PARPs) that are involved in DNA repair [5,[8][9][10].…”

Section: Introductionmentioning

confidence: 99%

“…These are FK866 and CHS 828 (now under development as the prodrug GMX1777 for intravenous, iv, administration [15]) which are both inhibitors of nicotinamide phosphoribosyl transferase (Nampt), a crucial step in the synthesis of NAD from nicotinamide [6,18].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Safety and efficacy of NAD depleting cancer drugs: results of a phase I clinical trial of CHS 828 and overview of published data

Heideman

Berglund

Larsson

et al. 2009

Cancer Chemother Pharmacol

163

150

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2 AbstractPurpose Depletion of cellular nicotinamide adenine dinucleotide (NAD) by inhibition of its synthesis is a new pharmacological principle for cancer treatment currently in early phases of clinical development. We present new and previously published data on the safety and efficacy of these drugs based on early clinical trials. Conclusions Critical toxicity from NAD depleting cancer drugs to consider in future trials seems to be thrombocytopenia and various gastrointestinal symptoms. Efficacy of NAD depleting drugs when used alone is expected to be low. Methods

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Safety and efficacy of NAD depleting cancer drugs: results of a phase I clinical trial of CHS 828 and overview of published data

Heideman

Berglund

Larsson

et al. 2009

Cancer Chemother Pharmacol

163

150

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“…10,11) However, these compounds were discovered by chance using cell-based assay, 12,13) and discovery of new NAMPT inhibitors with better structures has been hindered by the difficulty of conducting high-throughput screening (HTS) with good sensitivity. HTS presents difficulties because a radioisotope (RI)-labeled substrate is needed to retain good assay sensitivity, but a complicated procedure including separation of product from substrate prevents evaluation of large numbers of compounds.…”

mentioning

confidence: 99%

Discovery of a Novel Nicotinamide Phosphoribosyl Transferase (NAMPT) Inhibitor <i>via</i> <i>in Silico</i> Screening

Takeuchi

Niimi

Masumoto

et al. 2014

Biological & Pharmaceutical Bulletin

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Nicotinamide phosphoribosyl transferase (NAMPT) is a key enzyme in the salvage pathway of mammalian nicotinamide adenine dinucleotide (NAD) biosynthesis, catalyzing the synthesis of nicotinamide mononucleotide from nicotinamide (Nam). The diverse functions of NAD suggest that NAMPT inhibitors are potential drug candidates as anticancer agents, immunomodulators, or other agents. However, difficulty in conducting high-throughput NAMPT assay with good sensitivity has hampered the discovery of novel anti-NAMPT drugs with improved profiles. We combined an in silico screening strategy with a radioisotope (RI)-based enzyme assay and rationally identified promising NAMPT inhibitors with novel structures. AS1604498 was the most potent inhibitor, with an IC 50 of 44 nM, and inhibited THP-1 and K562 cell line growth with the IC 50 of 198 nM and 673 nM, respectively. The mode of action was found to reduce intracellular NAD following apoptosis, suggesting that these compounds inhibit NAMPT in cell-based assay. This strategy can be used to discover new drug candidates with targets which are difficult to assess through high-throughput screening. Our hit compounds may be used as seed compounds for developing new therapeutics with NAMPT.Key words nicotinamide phosphoribosyl transferase; in silico screening; FK866; nicotinamide adenine dinucleotide Nicotinamide phosphoribosyl transferase (NAMPT) catalyzes a rate-limiting step in the salvage pathway of mammalian nicotinamide adenine dinucleotide (NAD) biosynthesis. Recently, intracellular NAD has received substantial attention due to the recent discovery that several enzymes, including poly(ADP-ribose) polymerase (PARP) and the Sirtuin-family proteins, use NAD as a substrate, [1][2][3] suggesting that intracellular NAD level may regulate cytokine production, 4) circadian rhythm, 5,6) metabolism, and aging 3,7) through these enzymes. FK866, an NAMPT inhibitor, has been shown to induce apoptosis of cancer cells 8) and immune cells, 9) suggesting the possibility of NAMPT inhibitors as a novel drug class. As such, FK866 and CHS-828, another NAMPT inhibitor, are currently being investigated in clinical trials for cancer treatment.10,11) However, these compounds were discovered by chance using cell-based assay, 12,13) and discovery of new NAMPT inhibitors with better structures has been hindered by the difficulty of conducting high-throughput screening (HTS) with good sensitivity. HTS presents difficulties because a radioisotope (RI)-labeled substrate is needed to retain good assay sensitivity, but a complicated procedure including separation of product from substrate prevents evaluation of large numbers of compounds.Here we report our finding of novel compounds with potent NAMPT inhibitory activity as determined using in silico screening and a 96-well-based sensitive RI-based assay.

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“…In this context inhibition of NAMPT appears to represent a striking tool in anti-tumor therapies. At present two pharmacological inhibitors are under investigation: FK866 and CHS-828 (50). In clinical studies with patients harboring different highly advanced malignancies resistant to common therapies the pharmacokinetics and the action of the inhibitors showed large variations among patients.…”

Section: Discussionmentioning

confidence: 99%

Nicotinamide phosphoribosyltransferase and prostaglandin H2 synthase 2 are up-regulated in human pancreatic adenocarcinoma cells after stimulation with interleukin-1

Bauer

Venz²,

Junker³

et al. 2009

Int J Oncol

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Abstract. Human pancreatic cancer is today an almost incurable disease with a 5-year survival rate of <5%. Chronic inflammation in the tumor region is often associated with cancer progression. In pancreatic tumors, the pro-inflammatory cytokine IL-1 has been found to affect the development of chemoresistance in this cancer type. In a search for new therapeutic targets we investigated the effect of this proinflammatory mediator on pancreatic cancer protein expression. Therefore, the human pancreatic adenocarcinoma cell line Colo357 was subjected to proteomic analysis after stimulation with IL-1 using 2D gel electrophoresis and mass spectrometry. We detected 11 spots as being differentially expressed after stimulation with IL-1 representing 11 different proteins. Among them, nicotinamide phosphoribosyltransferase (NAMPT) and prostaglandin H 2 synthase 2 (PGHS-2) are crucial proteins whose expression in Colo357 is increased by IL-1. This study is the first one demonstrating an up-regulation of NAMPT in a tumor model for human pancreatic cancer. Several clinical trials using selective PGHS-2 or NAMPT inhibitors alone did not lead to an improvement in clinical outcome. Against the background of a high cardiovascular risk associated with PGHS-2-specific pharmacological inhibitors, we recommend a combinatory treatment with selective NAMPT and PGHS-2 inhibitors. This might overcome the limitations associated with PGHS-2 inhibitors since agents at low doses and with complementary mechanisms will be used. Such combined administration should positively affect the balance between risk and benefit in fighting the interplay of tumor-associated pancreatic inflammation and carcinogenesis in high-risk patients with pancreatic neoplasia. IntroductionPancreatic cancer is the fourth cause of cancer-related mortality in the USA and the sixth one in Europe with more than 250,000 patients estimated to die of the disease worldwide (1). This cancer entity is one of the most deadly of all malignancies with a death to incidence ratio approaching one making mortality rate a robust approximation of incidence for pancreatic cancer (2). The incidence of pancreatic cancer correlates with increasing age reaching a peak in the 65-75-years old age group (3). Approximately three-fourths of patients will die within one year of diagnosis and <5% survive up to 5 years after diagnosis (4). The poor outcome of pancreatic cancer is reflected by non-resectable primary lesions, locally advanced tumors, and a high metastatic potential (5). Since only a few patients benefit from classical adjuvant chemo-and radiotherapy, complete surgical resection is the superior treatment modality for patients with resectable disease. Unfortunately, the majority of pancreatic cancer patients present with locally advanced or metastatic tumors are not amenable for curative surgery. Only a disappointing 15% of patients at the time of diagnosis are eligible to undergo surgical excision, and even patients who have undergone such curative resection often die of recurrent carcin...

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Anticancer agent CHS-828 inhibits cellular synthesis of NAD

Cited by 114 publications

References 27 publications

Safety and efficacy of NAD depleting cancer drugs: results of a phase I clinical trial of CHS 828 and overview of published data

Safety and efficacy of NAD depleting cancer drugs: results of a phase I clinical trial of CHS 828 and overview of published data

Discovery of a Novel Nicotinamide Phosphoribosyl Transferase (NAMPT) Inhibitor <i>via</i> <i>in Silico</i> Screening

Nicotinamide phosphoribosyltransferase and prostaglandin H2 synthase 2 are up-regulated in human pancreatic adenocarcinoma cells after stimulation with interleukin-1

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