4D0X

Pyrrole-3-carboxamides as potent and selective JAK2 inhibitors

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.82 Å
  • R-Value Free: 0.219 
  • R-Value Work: 0.163 
  • R-Value Observed: 0.166 

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Ligand Structure Quality Assessment 


This is version 1.5 of the entry. See complete history. 


Literature

Pyrrole-3-Carboxamides as Potent and Selective Jak2 Inhibitors.

Brasca, M.G., Nesi, M., Avanzi, N., Ballinari, D., Bandiera, T., Bertrand, J., Bindi, S., Canevari, G., Carenzi, D., Casero, D., Ceriani, L., Ciomei, M., Cirla, A., Colombo, M., Cribioli, S., Cristiani, C., Della Vedova, F., Fachin, G., Fasolini, M., Felder, E.R., Galvani, A., Isacchi, A., Mirizzi, D., Motto, I., Panzeri, A., Pesenti, E., Vianello, P., Gnocchi, P., Donati, D.

(2014) Bioorg Med Chem 22: 4998

  • DOI: https://doi.org/10.1016/j.bmc.2014.06.025
  • Primary Citation of Related Structures:  
    4D0W, 4D0X, 4D1S

  • PubMed Abstract: 

    We report herein the discovery, structure guided design, synthesis and biological evaluation of a novel class of JAK2 inhibitors. Optimization of the series led to the identification of the potent and orally bioavailable JAK2 inhibitor 28 (NMS-P953). Compound 28 displayed significant tumour growth inhibition in SET-2 xenograft tumour model, with a mechanism of action confirmed in vivo by typical modulation of known biomarkers, and with a favourable pharmacokinetic and safety profile.

    • Organizational Affiliation: 

    Nerviano Medical Sciences S.r.l., Oncology, Viale Pasteur 10, 20014 Nerviano (MI), Italy. Electronic address: gabriella.brasca@nervianoms.com.


Macromolecules
Find similar proteins by: 
(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
TYROSINE-PROTEIN KINASE JAK2298Homo sapiensMutation(s): 0 
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 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
953
Query on 953
Download Ideal Coordinates CCD File 
B [auth A]5-(2-aminopyrimidin-4-yl)-2-[2-chloro-5-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide
C16 H11 Cl F3 N5 O
CZUQYAXYBOEHCY-UHFFFAOYSA-N
GOL
Query on GOL
Download Ideal Coordinates CCD File 
C [auth A]GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-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
953 Binding MOAD:  4D0X IC50: 8 (nM) from 1 assay(s)
BindingDB:  4D0X IC50: 8 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.82 Å
  • R-Value Free: 0.219 
  • R-Value Work: 0.163 
  • R-Value Observed: 0.166 
  • Space Group: C 2 2 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 93.07α = 90
b = 101.76β = 90
c = 67.71γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
SCALEPACKdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2014-07-23
    Type: Initial release
  • Version 1.1: 2014-09-10
    Changes: Database references
  • Version 1.2: 2017-09-27
    Changes: Data collection
  • Version 1.3: 2019-03-06
    Changes: Data collection, Derived calculations, Experimental preparation
  • Version 1.4: 2019-04-24
    Changes: Data collection, Source and taxonomy
  • Version 1.5: 2023-12-20
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description