5KIT | pdb_00005kit

Crystal Structure of Nicotinamide Phosphoribosyltransferase (Nampt) in Complex with Inhibitors 37


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.60 Å
  • R-Value Free: 
    0.180 (Depositor), 0.180 (DCC) 
  • R-Value Work: 
    0.137 (Depositor), 0.130 (DCC) 
  • R-Value Observed: 
    0.139 (Depositor) 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 

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This is version 1.2 of the entry. See complete history


Literature

Minimizing CYP2C9 Inhibition of Exposed-Pyridine NAMPT (Nicotinamide Phosphoribosyltransferase) Inhibitors.

Zak, M.Yuen, P.W.Liu, X.Patel, S.Sampath, D.Oeh, J.Liederer, B.M.Wang, W.O'Brien, T.Xiao, Y.Skelton, N.Hua, R.Sodhi, J.Wang, Y.Zhang, L.Zhao, G.Zheng, X.Ho, Y.C.Bair, K.W.Dragovich, P.S.

(2016) J Med Chem 59: 8345-8368

  • DOI: https://doi.org/10.1021/acs.jmedchem.6b00697
  • Primary Citation of Related Structures:  
    5KIT

  • PubMed Abstract: 

    NAMPT inhibitors may show potential as therapeutics for oncology. Throughout our NAMPT inhibitor program, we found that exposed pyridines or related heterocyclic systems in the left-hand portion of the inhibitors are necessary pharmacophores for potent cellular NAMPT inhibition. However, when combined with a benzyl group in the center of the inhibitors, such pyridine-like moieties also led to consistent and potent inhibition of CYP2C9. In an attempt to reduce CYP2C9 inhibition, a parallel synthesis approach was used to identify central benzyl group replacements with increased Fsp3. A spirocyclic central motif was thus discovered that was combined with left-hand pyridines (or pyridine-like systems) to provide cellularly potent NAMPT inhibitors with minimal CYP2C9 inhibition. Further optimization of potency and ADME properties led to the discovery of compound 68, a highly potent NAMPT inhibitor with outstanding efficacy in a mouse tumor xenograft model and lacking measurable CYP2C9 inhibition at the concentrations tested.


  • Organizational Affiliation

    Genentech Inc. , 1 DNA Way, South San Francisco, California 94080, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Nicotinamide phosphoribosyltransferase
A, B
491Homo 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 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
6TA
Query on 6TA

Download Ideal Coordinates CCD File 
C [auth A],
K [auth B]
~{tert}-butyl (2~{S})-2-[(1,3-dihydropyrrolo[3,4-c]pyridin-2-ylcarbonylamino)methyl]-6-azaspiro[2.5]octane-6-carboxylate
C21 H30 N4 O3
DLHHFYXNVIMXSY-QGZVFWFLSA-N
PO4
Query on PO4

Download Ideal Coordinates CCD File 
D [auth A]
E [auth A]
J [auth A]
L [auth B]
M [auth B]
PHOSPHATE ION
O4 P
NBIIXXVUZAFLBC-UHFFFAOYSA-K
EDO
Query on EDO

Download Ideal Coordinates CCD File 
F [auth A]
G [auth A]
H [auth A]
I [auth A]
N [auth B]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
6TA BindingDB:  5KIT IC50: min: 1, max: 47.9 (nM) from 10 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.60 Å
  • R-Value Free:  0.180 (Depositor), 0.180 (DCC) 
  • R-Value Work:  0.137 (Depositor), 0.130 (DCC) 
  • R-Value Observed: 0.139 (Depositor) 
Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 60.748α = 90
b = 106.589β = 96.65
c = 83.32γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
HKL-2000data reduction
SCALEPACKdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted 6TAClick on this verticalbar to view details

Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2016-08-31
    Type: Initial release
  • Version 1.1: 2016-10-05
    Changes: Database references
  • Version 1.2: 2024-03-06
    Changes: Data collection, Database references, Derived calculations