Analogues of 4-[(7-Bromo-2-methyl-4-oxo-3<i>H</i>-quinazolin-6-yl)methylprop-2-ynylamino]-<i>N</i>-(3-pyridylmethyl)benzamide (CB-30865) as Potent Inhibitors of Nicotinamide Phosphoribosyltransferase (Nampt)

Lockman, Jeffrey W.; Murphy, Brett R.; Zigar, Daniel F.; Judd, W. R.; Slattum, Paul M.; Gao, Zhong Hua; Ostanin, Kirill; Green, Jeremy; McKinnon, Rena; Terry-Lorenzo, Ryan T.; Fleischer, Tracey C.; Boniface, J. Jay; Shenderovich, Mark D.; Willardsen, J. Adam

doi:10.1021/jm101145b

Cited by 27 publications

(12 citation statements)

References 24 publications

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“…As shown in Figure 3 b, compound 3b displayed significantly weaker cell activity; the 50% effective concentration (EC 50 ) value was calculated to be 87.5 nM, which was approximately 200-fold higher than that of 3a (EC 50 = 0.48 nM). These results of the different inhibition degrees in cell-based assay from those in enzyme assay ( Figure 3 ) paralleled observations by others that the degrees of potency of cell-based assessments were not always identical with those of NAMPT enzymatic inhibition [ 26 , 28 , 47 ]. In addition, there was little cytotoxicity on non-cancer cell lines, such as TIG-120, WI38 and MRC-5 cells.…”

Section: Resultssupporting

confidence: 84%

Structural Basis of Beneficial Design for Effective Nicotinamide Phosphoribosyltransferase Inhibitors

et al. 2020

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Inhibition of nicotinamide phosphoribosyltransferase (NAMPT) is an attractive therapeutic strategy for targeting cancer metabolism. So far, many potent NAMPT inhibitors have been developed and shown to bind to two unique tunnel-shaped cavities existing adjacent to each active site of a NAMPT homodimer. However, cytotoxicities and resistances to NAMPT inhibitors have become apparent. Therefore, there remains an urgent need to develop effective and safe NAMPT inhibitors. Thus, we designed and synthesized two close structural analogues of NAMPT inhibitors, azaindole–piperidine (3a)- and azaindole–piperazine (3b)-motif compounds, which were modified from the well-known NAMPT inhibitor FK866 (1). Notably, 3a displayed considerably stronger enzyme inhibitory activity and cellular potency than did 3b and 1. The main reason for this phenomenon was revealed to be due to apparent electronic repulsion between the replaced nitrogen atom (N1) of piperazine in 3b and the Nδ atom of His191 in NAMPT by our in silico binding mode analyses. Indeed, 3b had a lower binding affinity score than did 3a and 1, although these inhibitors took similar stable chair conformations in the tunnel region. Taken together, these observations indicate that the electrostatic enthalpy potential rather than entropy effects inside the tunnel cavity has a significant impact on the different binding affinity of 3a from that of 3b in the disparate enzymatic and cellular potencies. Thus, it is better to avoid or minimize interactions with His191 in designing further effective NAMPT inhibitors.

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Section: Resultssupporting

confidence: 84%

Structural Basis of Beneficial Design for Effective Nicotinamide Phosphoribosyltransferase Inhibitors

et al. 2020

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“…Using LC-MS/MS, this protein was identified as NAMPT [114]. CB30865 and its derivative MPI-0479883 inhibit NAMPT through interactions with their pyridine ring moieties [114,115]. These findings coincided with studies on APO866, where it was discovered that the pyridyl moiety of APO866 stacks between the aromatic rings of Phe193 and Tyr18, functionally substituting for the pyridine ring present in both NAM and NMN [104].…”

Section: Cb-30865mentioning

confidence: 62%

PBEF/NAMPT/Visfatin: A Promising Drug Target For Treating Rheumatoid Arthritis?

2012

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NAMPT, also known as pre-B-cell colony-enhancing factor and visfatin, has been proposed to be involved in preventing apoptosis in cancer cells and, as such, has received a great deal of attention in recent years and stimulated the development to specific inhibitors for treating cancer. The role of NAMPT inhibitors as potential therapeutic agents for other diseases has not been studied extensively. Here, we describe their applicability for treating rheumatoid arthritis. We summarize current knowledge of NAMPT expression in healthy and diseased tissues, thereafter, we focus on pathological mechanisms relevant to rheumatoid arthritis that involve the NAMPT pathway and review the current status of NAMPT inhibitors being evaluated in clinical trials.

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“…Discovery Studio Client v2.5.0 was applied to create pharmacophore models and screen library in our work. Prior to create models, we collected a group of 77 existing NAMPT inhibitors from six literatures [5,[11][12][13][14][15] based on certain principles including spanning at least 4 orders of magnitude (0.00055 -2 μM) and the diversity of scaffolds. Subsequently, these inhibitors were divided into two sets: training set (25 molecules, shown in Fig.…”

Section: Preparation Of Training Set and Test Set Moleculesmentioning

confidence: 99%

Discovery of Novel NAMPT Inhibitors Based on Pharmacophore Modeling and Virtual Screening Techniques

Yi¹,

Zhou²,

Shao³

et al. 2015

CCHTS

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Nicotinamide phosphoribosyltransferase (NAMPT), an enzyme taking part in main NAD biosynthetic pathway, is an attractive target for anticancer therapy. The purpose of our study is to find novel NAMPT inhibitors based on in silico drug discovery means including the generation of 3D-QSAR models, and virtual screening techniques. Firstly, ten pharmacophore models were generated by Catalyst/HypoGen algorithm. Hypo1 with high correl value (0.96), large cost (77.77), and low root mean square deviation (0.81), featured by four chemical features was selected as the best one. Subsequently, Hypo1 was validated through test set prediction and Fischer's randomization methodologies. Then we screened some public compound libraries (Asinex, Ibscreen and Natural products database) using Hypo1 for a 3D query. The screened hits were further refined by Lipinski's rule of five, ADMET properties as well as molecular docking studies. Finally, six molecules with diverse scaffolds exhibited the right pharmacophore features and good binding modes between the receptor and ligands, and were selected as possible candidates against NAMPT for further study.

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Analogues of 4-[(7-Bromo-2-methyl-4-oxo-3H-quinazolin-6-yl)methylprop-2-ynylamino]-N-(3-pyridylmethyl)benzamide (CB-30865) as Potent Inhibitors of Nicotinamide Phosphoribosyltransferase (Nampt)

Cited by 27 publications

References 24 publications

Structural Basis of Beneficial Design for Effective Nicotinamide Phosphoribosyltransferase Inhibitors

Structural Basis of Beneficial Design for Effective Nicotinamide Phosphoribosyltransferase Inhibitors

PBEF/NAMPT/Visfatin: A Promising Drug Target For Treating Rheumatoid Arthritis?

Discovery of Novel NAMPT Inhibitors Based on Pharmacophore Modeling and Virtual Screening Techniques

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