NAPRT Expression Regulation Mechanisms: Novel Functions Predicted by a Bioinformatics Approach

Duarte-Pereira, Sara; Fajarda, Olga; Matos, Sérgio; Oliveira, José Luís; Silva, Raquel M.

doi:10.3390/genes12122022

Cited by 9 publications

(3 citation statements)

References 71 publications

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“…NAPRT displays marked tissue and tumor specificity in terms of expression and its regulation mechanisms and is mostly present in several catabolic healthy mammalian tissues including the heart, kidney, liver, and small intestine [ 19 , 25 , 30 , 31 , 32 , 33 ]. In tissues that express the NAPRT protein, NA is the preferred precursor of NAD.…”

Section: Introductionmentioning

confidence: 99%

Structure-Based Identification and Biological Characterization of New NAPRT Inhibitors

et al. 2022

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NAPRT, the rate-limiting enzyme of the Preiss–Handler NAD biosynthetic pathway, has emerged as a key biomarker for the clinical success of NAMPT inhibitors in cancer treatment. Previous studies found that high protein levels of NAPRT conferred resistance to NAMPT inhibition in several tumor types whereas the simultaneous blockade of NAMPT and NAPRT results in marked anti-tumor effects. While research has mainly focused on NAMPT inhibitors, the few available NAPRT inhibitors (NAPRTi) have a low affinity for the enzyme and have been scarcely characterized. In this work, a collection of diverse compounds was screened in silico against the NAPRT structure, and the selected hits were tested through cell-based assays in the NAPRT-proficient OVCAR-5 ovarian cell line and on the recombinant hNAPRT. We found different chemotypes that efficiently inhibit the enzyme in the micromolar range concentration and for which direct engagement with the target was verified by differential scanning fluorimetry. Of note, the therapeutic potential of these compounds was evidenced by a synergistic interaction between the NAMPT inhibitor FK866 and the new NAPRTi in terms of decreasing OVCAR-5 intracellular NAD levels and cell viability. For example, compound IM29 can potentiate the effect of FK866 of more than two-fold in reducing intracellular NAD levels. These results pave the way for the development of a new generation of human NAPRTi with anticancer activity.

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Section: Introductionmentioning

confidence: 99%

Structure-Based Identification and Biological Characterization of New NAPRT Inhibitors

et al. 2022

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“…The benzimidazole ring is ionized at physiological pH and engages Asp320 A with a salt bridge and H-bonds. Asp320 A is indirectly connected through a tight H-bonding network to Arg318 A , a residue implicated in catalysis through mutagenesis [ 27 , 28 ]. Intriguingly, Arg318 is also perturbed by two reported inhibitors ( 10 and 12 in Figure 2 ) that share similar chemical moieties with our inhibitory scaffold.…”

Section: Resultsmentioning

confidence: 99%

Properly Substituted Benzimidazoles as a New Promising Class of Nicotinate Phosphoribosyltransferase (NAPRT) Modulators

et al. 2023

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The prevention of nicotinamide adenine dinucleotide (NAD) biosynthesis is considered an attractive therapeutic approach against cancer, considering that tumor cells are characterized by an increased need for NAD to fuel their reprogrammed metabolism. On the other hand, the decline of NAD is a hallmark of some pathological conditions, including neurodegeneration and metabolic diseases, and boosting NAD biosynthesis has proven to be of therapeutic relevance. Therefore, targeting the enzymes nicotinamide phosphoribosyltransferase (NAMPT) and nicotinate phosphoribosyltransferase (NAPRT), which regulate NAD biosynthesis from nicotinamide (NAM) and nicotinic acid (NA), respectively, is considered a promising strategy to modulate intracellular NAD pool. While potent NAMPT inhibitors and activators have been developed, the search for NAPRT modulators is still in its infancy. In this work, we report on the identification of a new class of NAPRT modulators bearing the 1,2-dimethylbenzimidazole scaffold properly substituted in position 5. In particular, compounds 24, 31, and 32 emerged as the first NAPRT activators reported so far, while 18 behaved as a noncompetitive inhibitor toward NA (Ki = 338 µM) and a mixed inhibitor toward phosphoribosyl pyrophosphate (PRPP) (Ki = 134 µM). From in vitro pharmacokinetic studies, compound 18 showed an overall good ADME profile. To rationalize the obtained results, docking studies were performed on the NAPRT structure. Moreover, a preliminary pharmacophore model was built to shed light on the shift from inhibitors to activators.

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“…Several studies have shown that NAMPT and NAD + are frequently upregulated in several human malignancies and play key roles in the development, progression, and recurrence of cancer (Lucena-Cacace et al, 2018 ; Zhang et al, 2019 ). Furthermore, unlike tumor cells, which mostly depend on NAMPT, normal cells can synthesize NAD + through other biosynthetic pathways, such as nicotinic acid phosphoribosyltransferase (NAPRT) (Duarte-Pereira et al, 2021 ). NAMPT and NAD + not only affect tumor metabolism but also affect the tumor immune microenvironment.…”

Section: Introductionmentioning

confidence: 99%

The regulatory relationship between NAMPT and PD-L1 in cancer and identification of a dual-targeting inhibitor

Yang,

Li,

Wang

et al. 2024

EMBO Mol Med

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Cancer is a heterogeneous disease. Although both tumor metabolism and tumor immune microenvironment are recognized as driving factors in tumorigenesis, the relationship between them is still not well-known, and potential combined targeting approaches remain to be identified. Here, we demonstrated a negative correlation between the expression of NAMPT, an NAD+ metabolism enzyme, and PD-L1 expression in various cancer cell lines. A clinical study showed that a NAMPTHigh PD-L1Low expression pattern predicts poor prognosis in patients with various cancers. In addition, pharmacological inhibition of NAMPT results in the transcription upregulation of PD-L1 by SIRT-mediated acetylation change of NF-κB p65, and blocking PD-L1 would induce NAMPT expression through a HIF-1-dependent glycolysis pathway. Based on these findings, we designed and synthesized a dual NAMPT/PD-L1 targeting compound, LZFPN-90, which inhibits cell growth in a NAMPT-dependent manner and blocks the cell cycle, subsequently inducing apoptosis. Under co-culture conditions, LZFPN-90 treatment contributes to the proliferation and activation of T cells and blocks the growth of cancer cells. Using mice bearing genetically manipulated tumors, we confirmed that LZFPN-90 exerted target-dependent antitumor activities, affecting metabolic processes and the immune system. In conclusion, our results demonstrate the relevance of NAD+-related metabolic processes in antitumor immunity and suggest that co-targeting NAD+ metabolism and PD-L1 represents a promising therapeutic approach.

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NAPRT Expression Regulation Mechanisms: Novel Functions Predicted by a Bioinformatics Approach

Cited by 9 publications

References 71 publications

Structure-Based Identification and Biological Characterization of New NAPRT Inhibitors

Structure-Based Identification and Biological Characterization of New NAPRT Inhibitors

Properly Substituted Benzimidazoles as a New Promising Class of Nicotinate Phosphoribosyltransferase (NAPRT) Modulators

The regulatory relationship between NAMPT and PD-L1 in cancer and identification of a dual-targeting inhibitor

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