5M7M

Novel Imidazo[1,2-a]pyridine Derivatives with Potent Autotaxin/ENPP2 Inhibitor Activity


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.70 Å
  • R-Value Free: 0.284 
  • R-Value Work: 0.229 
  • R-Value Observed: 0.232 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 2.0 of the entry. See complete history


Literature

Discovery, Structure-Activity Relationship, and Binding Mode of an Imidazo[1,2-a]pyridine Series of Autotaxin Inhibitors.

Joncour, A.Desroy, N.Housseman, C.Bock, X.Bienvenu, N.Cherel, L.Labeguere, V.Peixoto, C.Annoot, D.Lepissier, L.Heiermann, J.Hengeveld, W.J.Pilzak, G.Monjardet, A.Wakselman, E.Roncoroni, V.Le Tallec, S.Galien, R.David, C.Vandervoort, N.Christophe, T.Conrath, K.Jans, M.Wohlkonig, A.Soror, S.Steyaert, J.Touitou, R.Fleury, D.Vercheval, L.Mollat, P.Triballeau, N.van der Aar, E.Brys, R.Heckmann, B.

(2017) J Med Chem 60: 7371-7392

  • DOI: https://doi.org/10.1021/acs.jmedchem.7b00647
  • Primary Citation of Related Structures:  
    5M7M

  • PubMed Abstract: 

    Autotaxin (ATX) is a secreted enzyme playing a major role in the production of lysophosphatidic acid (LPA) in blood through hydrolysis of lysophosphatidyl choline (LPC). The ATX-LPA signaling axis arouses a high interest in the drug discovery industry as it has been implicated in several diseases including cancer, fibrotic diseases, and inflammation, among others. An imidazo[1,2-a]pyridine series of ATX inhibitors was identified out of a high-throughput screening (HTS). A cocrystal structure with one of these compounds and ATX revealed a novel binding mode with occupancy of the hydrophobic pocket and channel of ATX but no interaction with zinc ions of the catalytic site. Exploration of the structure-activity relationship led to compounds displaying high activity in biochemical and plasma assays, exemplified by compound 40. Compound 40 was also able to decrease the plasma LPA levels upon oral administration to rats.


  • Organizational Affiliation

    Galapagos SASU , 102 Avenue Gaston Roussel, 93230 Romainville, France.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Ectonucleotide pyrophosphatase/phosphodiesterase family member 2871Homo sapiensMutation(s): 1 
Gene Names: ENPP2ATXPDNP2
EC: 3.1.4.39
UniProt & NIH Common Fund Data Resources
Find proteins for Q13822 (Homo sapiens)
Explore Q13822 
Go to UniProtKB:  Q13822
PHAROS:  Q13822
GTEx:  ENSG00000136960 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ13822
Sequence Annotations
Expand
  • Reference Sequence
Oligosaccharides

Help

Entity ID: 2
MoleculeChains Length2D Diagram Glycosylation3D Interactions
alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-alpha-D-mannopyranose-(1-6)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose
B
6N-Glycosylation
Glycosylation Resources
GlyTouCan:  G47410OF
GlyCosmos:  G47410OF
GlyGen:  G47410OF
Small Molecules
Ligands 8 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
7HR
Query on 7HR

Download Ideal Coordinates CCD File 
C [auth A]~{N}-[6-[1-[3-(dimethylamino)propylsulfonyl]piperidin-4-yl]-2-ethyl-imidazo[1,2-a]pyridin-3-yl]-4-(4-fluorophenyl)-~{N}-methyl-1,3-thiazol-2-amine
C29 H37 F N6 O2 S2
UBTDMKAOXXTVRQ-UHFFFAOYSA-N
IOD
Query on IOD

Download Ideal Coordinates CCD File 
D [auth A]IODIDE ION
I
XMBWDFGMSWQBCA-UHFFFAOYSA-M
PO4
Query on PO4

Download Ideal Coordinates CCD File 
H [auth A]PHOSPHATE ION
O4 P
NBIIXXVUZAFLBC-UHFFFAOYSA-K
ZN
Query on ZN

Download Ideal Coordinates CCD File 
K [auth A],
L [auth A],
M [auth A],
N [auth A]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
NI
Query on NI

Download Ideal Coordinates CCD File 
G [auth A]
O [auth A]
P [auth A]
Q [auth A]
R [auth A]
G [auth A],
O [auth A],
P [auth A],
Q [auth A],
R [auth A],
S [auth A],
T [auth A]
NICKEL (II) ION
Ni
VEQPNABPJHWNSG-UHFFFAOYSA-N
SCN
Query on SCN

Download Ideal Coordinates CCD File 
F [auth A]THIOCYANATE ION
C N S
ZMZDMBWJUHKJPS-UHFFFAOYSA-M
K
Query on K

Download Ideal Coordinates CCD File 
J [auth A]POTASSIUM ION
K
NPYPAHLBTDXSSS-UHFFFAOYSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
E [auth A],
I [auth A]
CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Binding Affinity Annotations 
IDSourceBinding Affinity
7HR BindingDB:  5M7M IC50: min: 50, max: 357 (nM) from 3 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.70 Å
  • R-Value Free: 0.284 
  • R-Value Work: 0.229 
  • R-Value Observed: 0.232 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 77.45α = 90
b = 78.89β = 91.87
c = 78.57γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
XDSdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2017-08-30
    Type: Initial release
  • Version 1.1: 2017-09-27
    Changes: Database references
  • Version 1.2: 2018-01-31
    Changes: Database references
  • Version 2.0: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Atomic model, Data collection, Derived calculations, Structure summary