4JR5

Structure-based Identification of Ureas as Novel Nicotinamide Phosphoribosyltransferase (Nampt) Inhibitors


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.91 Å
  • R-Value Free: 0.210 
  • R-Value Work: 0.163 
  • R-Value Observed: 0.165 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Structure-based identification of ureas as novel nicotinamide phosphoribosyltransferase (nampt) inhibitors.

Zheng, X.Bauer, P.Baumeister, T.Buckmelter, A.J.Caligiuri, M.Clodfelter, K.H.Han, B.Ho, Y.C.Kley, N.Lin, J.Reynolds, D.J.Sharma, G.Smith, C.C.Wang, Z.Dragovich, P.S.Oh, A.Wang, W.Zak, M.Gunzner-Toste, J.Zhao, G.Yuen, P.W.Bair, K.W.

(2013) J Med Chem 56: 4921-4937

  • DOI: https://doi.org/10.1021/jm400186h
  • Primary Citation of Related Structures:  
    4JR5, 4KFN, 4KFO

  • PubMed Abstract: 

    Nicotinamide phosphoribosyltransferase (Nampt) is a promising anticancer target. Virtual screening identified a thiourea analogue, compound 5, as a novel highly potent Nampt inhibitor. Guided by the cocrystal structure of 5, SAR exploration revealed that the corresponding urea compound 7 exhibited similar potency with an improved solubility profile. These studies also indicated that a 3-pyridyl group was the preferred substituent at one inhibitor terminus and also identified a urea moiety as the optimal linker to the remainder of the inhibitor structure. Further SAR optimization of the other inhibitor terminus ultimately yielded compound 50 as a urea-containing Nampt inhibitor which exhibited excellent biochemical and cellular potency (enzyme IC50 = 0.007 μM; A2780 IC50 = 0.032 μM). Compound 50 also showed excellent in vivo antitumor efficacy when dosed orally in an A2780 ovarian tumor xenograft model (TGI of 97% was observed on day 17).


  • Organizational Affiliation

    Forma Therapeutics, Inc., 500 Arsenal Street, Watertown, Massachusetts 02472, USA. [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 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
1LS
Query on 1LS

Download Ideal Coordinates CCD File 
C [auth A],
G [auth B]
1-[4-(piperidin-1-ylsulfonyl)phenyl]-3-(pyridin-3-ylmethyl)thiourea
C18 H22 N4 O2 S2
NIADLWNDYLCGNO-UHFFFAOYSA-N
PO4
Query on PO4

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

Download Ideal Coordinates CCD File 
F [auth A],
J [auth B]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
1LS BindingDB:  4JR5 IC50: min: 7, max: 9.9 (nM) from 2 assay(s)
PDBBind:  4JR5 IC50: 7 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.91 Å
  • R-Value Free: 0.210 
  • R-Value Work: 0.163 
  • R-Value Observed: 0.165 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 60.631α = 90
b = 106.739β = 96.65
c = 83.174γ = 90
Software Package:
Software NamePurpose
ADSCdata collection
PHASERphasing
PHENIXrefinement
XDSdata reduction
SCALAdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2013-05-08
    Type: Initial release
  • Version 1.1: 2013-06-26
    Changes: Database references
  • Version 1.2: 2013-07-10
    Changes: Database references
  • Version 1.3: 2024-02-28
    Changes: Data collection, Database references, Derived calculations