Fragment-Based Identification of Amides Derived from <i>trans</i>-2-(Pyridin-3-yl)cyclopropanecarboxylic Acid as Potent Inhibitors of Human Nicotinamide Phosphoribosyltransferase (NAMPT)

Giannetti, Anthony M.; Zheng, Xiaozhang; Skelton, Nicholas J.; Wang, Weiru; Bravo, Brandon; Bair, Kenneth W.; Baumeister, Timm; Cheng, Elaine; Crocker, Lisa; Feng, Y.; Gunzner-Toste, Janet; Ho, Yew Kam; Hua, Rongbao; Liederer, Bianca M.; Liu, Yongbo; Ma, Xiaolei; O’Brien, Thomas G.; Oeh, Jason; Sampath, Deepak; Shen, Youming; Wang, Yuming; Wang, Leslie; Wu, Hongxing; Xiao, Yang; Yuen, Po‐wai; Zak, Mark; Zhao, Gui‐Ling; Zhao, Qiang; Dragovich, Peter S.

doi:10.1021/jm4015108

Cited by 35 publications

(11 citation statements)

References 59 publications

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“…The inhibition of NAMPT leads to suppression of tumour cell growth and induction of apoptosis due to NAD + depletion [ 53 ]. NAMPT represents a promising therapeutic target for the development of potential novel cancer drugs [ 54 , 55 ]. In most cancer cells, poly (ADP-ribose) polymerase is activated due to DNA damage and cell death induced by oxidative stress [ 56 , 57 ].…”

Section: Discussionmentioning

confidence: 99%

Metabolomic Profiling of the Synergistic Effects of Melittin in Combination with Cisplatin on Ovarian Cancer Cells

et al. 2017

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Melittin, the main peptide present in bee venom, has been proposed as having potential for anticancer therapy; the addition of melittin to cisplatin, a first line treatment for ovarian cancer, may increase the therapeutic response in cancer treatment via synergy, resulting in improved tolerability, reduced relapse, and decreased drug resistance. Thus, this study was designed to compare the metabolomic effects of melittin in combination with cisplatin in cisplatin-sensitive (A2780) and resistant (A2780CR) ovarian cancer cells. Liquid chromatography (LC) coupled with mass spectrometry (MS) was applied to identify metabolic changes in A2780 (combination treatment 5 μg/mL melittin + 2 μg/mL cisplatin) and A2780CR (combination treatment 2 μg/mL melittin + 10 μg/mL cisplatin) cells. Principal components analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) multivariate data analysis models were produced using SIMCA-P software. All models displayed good separation between experimental groups and high-quality goodness of fit (R2) and goodness of prediction (Q2), respectively. The combination treatment induced significant changes in both cell lines involving reduction in the levels of metabolites in the tricarboxylic acid (TCA) cycle, oxidative phosphorylation, purine and pyrimidine metabolism, and the arginine/proline pathway. The combination of melittin with cisplatin that targets these pathways had a synergistic effect. The melittin-cisplatin combination had a stronger effect on the A2780 cell line in comparison with the A2780CR cell line. The metabolic effects of melittin and cisplatin in combination were very different from those of each agent alone.

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Section: Discussionmentioning

confidence: 99%

Metabolomic Profiling of the Synergistic Effects of Melittin in Combination with Cisplatin on Ovarian Cancer Cells

et al. 2017

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“…These included compounds with a diaryl-sulfone moiety at one molecular terminus and a bicyclic heterocycle at the other (Series A) [18] , [19] , [21] . Other structurally-distinct compounds which incorporated cyanoguanidine groups were also utilized in these assessments (Series B) [25] as well as a molecule bearing a trans -cyclopropane moiety [26] (compound 12). Overall, the pattern of sensitivity to the various NAMPT mutations appears to depend primarily on the structure of the compound core and not the appended R1 and R2 groups ( Figure 4 b–c, Table 2 ).…”

Section: Resultsmentioning

confidence: 99%

Structural Basis for Resistance to Diverse Classes of NAMPT Inhibitors

Wang¹,

Elkins²,

Oh³

et al. 2014

PLoS ONE

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Inhibiting NAD biosynthesis by blocking the function of nicotinamide phosphoribosyl transferase (NAMPT) is an attractive therapeutic strategy for targeting tumor metabolism. However, the development of drug resistance commonly limits the efficacy of cancer therapeutics. This study identifies mutations in NAMPT that confer resistance to a novel NAMPT inhibitor, GNE-618, in cell culture and in vivo, thus demonstrating that the cytotoxicity of GNE-618 is on target. We determine the crystal structures of six NAMPT mutants in the apo form and in complex with various inhibitors and use cellular, biochemical and structural data to elucidate two resistance mechanisms. One is the surprising finding of allosteric modulation by mutation of residue Ser165, resulting in unwinding of an α-helix that binds the NAMPT substrate 5-phosphoribosyl-1-pyrophosphate (PRPP). The other mechanism is orthosteric blocking of inhibitor binding by mutations of Gly217. Furthermore, by evaluating a panel of diverse small molecule inhibitors, we unravel inhibitor structure activity relationships on the mutant enzymes. These results provide valuable insights into the design of next generation NAMPT inhibitors that offer improved therapeutic potential by evading certain mechanisms of resistance.

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“…Using fragment-based drug discovery (FBDD), − Kamada and coauthors conducted screens of 1494 fragment-sized molecules against four BCL6 BTB proteins: captured wt BCL6 BTB , captured mt BCL6 BTB , coupled wt BCL6 BTB and NeutrAvidin, using SPR. − From the identified hits, the authors chose 64 pan-active candidates and conducted full dose–responses. The binding of selected hits was confirmed by STD-NMR .…”

Section: Recent Development Of Bcl6btb Inhibitorsmentioning

confidence: 99%

Progress toward B-Cell Lymphoma 6 BTB Domain Inhibitors for the Treatment of Diffuse Large B-Cell Lymphoma and Beyond

Hwang

MacKerell

et al. 2021

J. Med. Chem.

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B-cell lymphoma 6 (BCL6) is a master regulator of germinal center formation that produce antibody-secreting plasma cells and memory B-cells for sustained immune responses. The BTB domain of BCL6 (BCL6BTB) forms a homodimer that mediates transcriptional repression by recruiting its corepressor proteins to form a biologically functional transcriptional complex. The protein–protein interaction (PPI) between the BCL6BTB and its corepressors has emerged as a therapeutic target for the treatment of DLBCL and a number of other human cancers. This Perspective provides an overview of recent advances in the development of BCL6BTB inhibitors from reversible inhibitors, irreversible inhibitors, to BCL6 degraders. Inhibitor design and medicinal chemistry strategies for the development of novel compounds will be provided. The binding mode of new inhibitors to BCL6BTB are highlighted. Also, the in vitro and in vivo assays used for the evaluation of new compounds will be discussed.

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Fragment-Based Identification of Amides Derived from trans-2-(Pyridin-3-yl)cyclopropanecarboxylic Acid as Potent Inhibitors of Human Nicotinamide Phosphoribosyltransferase (NAMPT)

Cited by 35 publications

References 59 publications

Metabolomic Profiling of the Synergistic Effects of Melittin in Combination with Cisplatin on Ovarian Cancer Cells

Metabolomic Profiling of the Synergistic Effects of Melittin in Combination with Cisplatin on Ovarian Cancer Cells

Structural Basis for Resistance to Diverse Classes of NAMPT Inhibitors

Progress toward B-Cell Lymphoma 6 BTB Domain Inhibitors for the Treatment of Diffuse Large B-Cell Lymphoma and Beyond

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