3RVG

Crystals structure of Jak2 with a 1-amino-5H-pyrido[4,3-b]indol-4-carboxamide inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.300 
  • R-Value Work: 0.221 
  • R-Value Observed: 0.225 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Discovery of 1-amino-5H-pyrido[4,3-b]indol-4-carboxamide inhibitors of Janus kinase 2 (JAK2) for the treatment of myeloproliferative disorders.

Lim, J.Taoka, B.Otte, R.D.Spencer, K.Dinsmore, C.J.Altman, M.D.Chan, G.Rosenstein, C.Sharma, S.Su, H.P.Szewczak, A.A.Xu, L.Yin, H.Zugay-Murphy, J.Marshall, C.G.Young, J.R.

(2011) J Med Chem 54: 7334-7349

  • DOI: https://doi.org/10.1021/jm200909u
  • Primary Citation of Related Structures:  
    3RVG

  • PubMed Abstract: 

    The JAK-STAT pathway mediates signaling by cytokines, which control survival, proliferation, and differentiation of a variety of cells. In recent years, a single point mutation (V617F) in the tyrosine kinase JAK2 was found to be present with a high incidence in myeloproliferative disorders (MPDs). This mutation led to hyperactivation of JAK2, cytokine-independent signaling, and subsequent activation of downstream signaling networks. The genetic, biological, and physiological evidence suggests that JAK2 inhibitors could be effective in treating MPDs. De novo design efforts of new scaffolds identified 1-amino-5H-pyrido[4,3-b]indol-4-carboxamides as a new viable lead series. Subsequent optimization of cell potency, metabolic stability, and off-target activities of the leads led to the discovery of 7-(2-aminopyrimidin-5-yl)-1-{[(1R)-1-cyclopropyl-2,2,2-trifluoroethyl]amino}-5H-pyrido[4,3-b]indole-4-carboxamide (65). Compound 65 is a potent, orally active inhibitor of JAK2 with excellent selectivity, PK profile, and in vivo efficacy in animal models.


  • Organizational Affiliation

    Department of Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States. jongwon_lim@merck.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Tyrosine-protein kinase JAK2303Homo sapiensMutation(s): 0 
Gene Names: JAK2
EC: 2.7.1.112 (PDB Primary Data), 2.7.10.2 (PDB Primary Data)
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
17P
Query on 17P

Download Ideal Coordinates CCD File 
B [auth A]1-(cyclohexylamino)-7-(1-methyl-1H-pyrazol-4-yl)-5H-pyrido[4,3-b]indole-4-carboxamide
C22 H24 N6 O
NSYNFVRSQTTZAL-UHFFFAOYSA-N
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
PTR
Query on PTR
A
L-PEPTIDE LINKINGC9 H12 N O6 PTYR
Binding Affinity Annotations 
IDSourceBinding Affinity
17P PDBBind:  3RVG IC50: 5 (nM) from 1 assay(s)
Binding MOAD:  3RVG IC50: 5 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.300 
  • R-Value Work: 0.221 
  • R-Value Observed: 0.225 
  • Space Group: P 65
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 124.433α = 90
b = 124.433β = 90
c = 36.734γ = 120
Software Package:
Software NamePurpose
PHENIXrefinement
PDB_EXTRACTdata extraction
JDirectordata collection
DENZOdata reduction
SCALEPACKdata scaling
HKL-2000data scaling
REFMACphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2012-03-21
    Type: Initial release
  • Version 1.1: 2017-11-08
    Changes: Refinement description