4N9E

Fragment-based Design of 3-Aminopyridine-derived Amides as Potent Inhibitors of Human Nicotinamide Phosphoribosyltransferase (NAMPT)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.72 Å
  • R-Value Free: 0.189 
  • R-Value Work: 0.153 
  • R-Value Observed: 0.155 

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Ligand Structure Quality Assessment 


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Literature

Fragment-based design of 3-aminopyridine-derived amides as potent inhibitors of human nicotinamide phosphoribosyltransferase (NAMPT).

Dragovich, P.S.Zhao, G.Baumeister, T.Bravo, B.Giannetti, A.M.Ho, Y.C.Hua, R.Li, G.Liang, X.Ma, X.O'Brien, T.Oh, A.Skelton, N.J.Wang, C.Wang, W.Wang, Y.Xiao, Y.Yuen, P.W.Zak, M.Zhao, Q.Zheng, X.

(2014) Bioorg Med Chem Lett 24: 954-962

  • DOI: https://doi.org/10.1016/j.bmcl.2013.12.062
  • Primary Citation of Related Structures:  
    4N9B, 4N9C, 4N9D, 4N9E

  • PubMed Abstract: 

    The fragment-based identification of two novel and potent biochemical inhibitors of the nicotinamide phosphoribosyltransferase (NAMPT) enzyme is described. These compounds (51 and 63) incorporate an amide moiety derived from 3-aminopyridine, and are thus structurally distinct from other known anti-NAMPT agents. Each exhibits potent inhibition of NAMPT biochemical activity (IC50=19 and 15 nM, respectively) as well as robust antiproliferative properties in A2780 cell culture experiments (IC50=121 and 99 nM, respectively). However, additional biological studies indicate that only inhibitor 51 exerts its A2780 cell culture effects via a NAMPT-mediated mechanism. The crystal structures of both 51 and 63 in complex with NAMPT are also independently described.


  • Organizational Affiliation

    Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: [email protected].


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Nicotinamide phosphoribosyltransferase
A, B
501Homo sapiensMutation(s): 0 
Gene Names: NAMPTPBEFPBEF1
EC: 2.4.2.12
UniProt & NIH Common Fund Data Resources
Find proteins for P43490 (Homo sapiens)
Explore P43490 
Go to UniProtKB:  P43490
PHAROS:  P43490
GTEx:  ENSG00000105835 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP43490
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
2HL
Query on 2HL

Download Ideal Coordinates CCD File 
C [auth A],
S [auth B]
1-[(1-benzoylpiperidin-4-yl)methyl]-N-(pyridin-3-yl)-1H-benzimidazole-5-carboxamide
C26 H25 N5 O2
UROBXDPDOFZURE-UHFFFAOYSA-N
DTT
Query on DTT

Download Ideal Coordinates CCD File 
Q [auth A],
R [auth A]
2,3-DIHYDROXY-1,4-DITHIOBUTANE
C4 H10 O2 S2
VHJLVAABSRFDPM-IMJSIDKUSA-N
PO4
Query on PO4

Download Ideal Coordinates CCD File 
D [auth A],
T [auth B]
PHOSPHATE ION
O4 P
NBIIXXVUZAFLBC-UHFFFAOYSA-K
EDO
Query on EDO

Download Ideal Coordinates CCD File 
AA [auth B]
BA [auth B]
E [auth A]
F [auth A]
G [auth A]
AA [auth B],
BA [auth B],
E [auth A],
F [auth A],
G [auth A],
H [auth A],
I [auth A],
J [auth A],
K [auth A],
L [auth A],
M [auth A],
N [auth A],
O [auth A],
P [auth A],
U [auth B],
V [auth B],
W [auth B],
X [auth B],
Y [auth B],
Z [auth B]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
2HL BindingDB:  4N9E IC50: min: 15, max: 1000 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.72 Å
  • R-Value Free: 0.189 
  • R-Value Work: 0.153 
  • R-Value Observed: 0.155 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 60.459α = 90
b = 106.401β = 96.52
c = 83.092γ = 90
Software Package:
Software NamePurpose
HKL-2000data collection
PHASERphasing
PHENIXrefinement
DENZOdata reduction
SCALEPACKdata scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2014-02-19
    Type: Initial release
  • Version 1.1: 2024-02-28
    Changes: Data collection, Database references, Derived calculations