5CF8

CRYSTAL STRUCTURE OF JANUS KINASE 2 IN COMPLEX WITH N,N-DICYCLOPROPYL-10-ETHYL-7-[(3-METHOXYPROPYL)AMINO] -3-METHYL-3,5,8,10-TETRAAZATRICYCLO[7.3.0.0,6] DODECA-1(9),2(6),4,7,11-PENTAENE-11-CARBOXAMIDE

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.204 
  • R-Value Work: 0.191 
  • R-Value Observed: 0.191 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history. 


Literature

Discovery of a Highly Selective JAK2 Inhibitor, BMS-911543, for the Treatment of Myeloproliferative Neoplasms.

Wan, H., Schroeder, G.M., Hart, A.C., Inghrim, J., Grebinski, J., Tokarski, J.S., Lorenzi, M.V., You, D., Mcdevitt, T., Penhallow, B., Vuppugalla, R., Zhang, Y., Gu, X., Iyer, R., Lombardo, L.J., Trainor, G.L., Ruepp, S., Lippy, J., Blat, Y., Sack, J.S., Khan, J.A., Stefanski, K., Sleczka, B., Mathur, A., Sun, J.H., Wong, M.K., Wu, D.R., Li, P., Gupta, A., Arunachalam, P.N., Pragalathan, B., Narayanan, S., K C, N., Kuppusamy, P., Purandare, A.V.

(2015) ACS Med Chem Lett 6: 850-855

  • DOI: https://doi.org/10.1021/acsmedchemlett.5b00226
  • Primary Citation of Related Structures:  
    5CF8

  • PubMed Abstract: 

    JAK2 kinase inhibitors are a promising new class of agents for the treatment of myeloproliferative neoplasms and have potential for the treatment of other diseases possessing a deregulated JAK2-STAT pathway. X-ray structure and ADME guided refinement of C-4 heterocycles to address metabolic liability present in dialkylthiazole 1 led to the discovery of a clinical candidate, BMS-911543 (11), with excellent kinome selectivity, in vivo PD activity, and safety profile.

    • Organizational Affiliation: 

    Bristol-Myers Squibb R&D , US Route 206 and Province Line Road, Princeton, New Jersey 08543-4000, United States.


Macromolecules
Find similar proteins by: 
(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Tyrosine-protein kinase JAK2
A, B
301Homo sapiensMutation(s): 0 
Gene Names: JAK2
EC: 2.7.10.2
UniProt & NIH Common Fund Data Resources
Find proteins for O60674 (Homo sapiens)
Explore O60674 
Go to UniProtKB:  O60674
PHAROS:  O60674
GTEx:  ENSG00000096968 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO60674
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
50V
Query on 50V
Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]		N,N-dicyclopropyl-4-[(1,5-dimethyl-1H-pyrazol-3-yl)amino]-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide
C23 H28 N8 O
JCINBYQJBYJGDM-UHFFFAOYSA-N
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
PTR
Query on PTR
A, B
L-PEPTIDE LINKINGC9 H12 N O6 PTYR
Binding Affinity Annotations 
IDSourceBinding Affinity
50V BindingDB:  5CF8 Kd: 0.48 (nM) from 1 assay(s)
IC50: min: 1.1, max: 80 (nM) from 3 assay(s)
Binding MOAD:  5CF8 IC50: 1.1 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.204 
  • R-Value Work: 0.191 
  • R-Value Observed: 0.191 
  • Space Group: P 41
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 112.16α = 90
b = 112.16β = 90
c = 70.67γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
HKL-2000data reduction
HKL-2000data scaling
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

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Ligand Structure Quality Assessment 


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Entry History 

Deposition Data

  • Released Date: 2015-08-26 
    • Deposition Author(s): Sack, J.S.

Revision History  (Full details and data files)

  • Version 1.0: 2015-08-26
    Type: Initial release
  • Version 1.1: 2015-09-02
    Changes: Database references
  • Version 1.2: 2017-11-22
    Changes: Derived calculations, Refinement description