4LWW

Discovery of Potent and Efficacious Cyanoguanidine-containing Nicotinamide Phosphoribosyltransferase (Nampt) Inhibitors


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.64 Å
  • R-Value Free: 0.179 
  • R-Value Work: 0.154 
  • R-Value Observed: 0.155 

Starting Model: experimental
View more details

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Discovery of potent and efficacious cyanoguanidine-containing nicotinamide phosphoribosyltransferase (Nampt) inhibitors.

Zheng, X.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.Wang, Y.Yuen, P.W.Bair, K.W.

(2014) Bioorg Med Chem Lett 24: 337-343

  • DOI: https://doi.org/10.1016/j.bmcl.2013.11.006
  • Primary Citation of Related Structures:  
    4LTS, 4LWW

  • PubMed Abstract: 

    A co-crystal structure of amide-containing compound (4) in complex with the nicotinamide phosphoribosyltransferase (Nampt) protein and molecular modeling were utilized to design and discover a potent novel cyanoguanidine-containing inhibitor bearing a sulfone moiety (5, Nampt Biochemical IC50=2.5nM, A2780 cell proliferation IC50=9.7nM). Further SAR exploration identified several additional cyanoguanidine-containing compounds with high potency and good microsomal stability. Among these, compound 15 was selected for in vivo profiling and demonstrated good oral exposure in mice. It also exhibited excellent in vivo antitumor efficacy when dosed orally in an A2780 ovarian tumor xenograft model. The co-crystal structure of this compound in complex with the NAMPT protein was also determined.


  • Organizational Affiliation

    Forma Therapeutics, Inc., 500 Arsenal Street, Watertown, MA 02472, 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 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
LWW
Query on LWW

Download Ideal Coordinates CCD File 
C [auth A],
O [auth B]
N-(4-(phenylsulfonyl)benzyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide
C21 H17 N3 O3 S
LGQSNALVWIMFPP-UHFFFAOYSA-N
PO4
Query on PO4

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

Download Ideal Coordinates CCD File 
AA [auth B]
F [auth A]
G [auth A]
H [auth A]
I [auth A]
AA [auth B],
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],
R [auth B],
S [auth B],
T [auth B],
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
LWW PDBBind:  4LWW IC50: 29 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.64 Å
  • R-Value Free: 0.179 
  • R-Value Work: 0.154 
  • R-Value Observed: 0.155 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 60.426α = 90
b = 106.287β = 96.45
c = 83.049γ = 90
Software Package:
Software NamePurpose
HKL-2000data collection
PHASERphasing
PHENIXrefinement
DENZOdata reduction
SCALEPACKdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2013-12-25
    Type: Initial release
  • Version 1.1: 2014-01-15
    Changes: Database references
  • Version 1.2: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description