4BGH

Crystal Structure of CDK2 in complex with pan-CDK Inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.246 
  • R-Value Work: 0.193 
  • R-Value Observed: 0.196 

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Ligand Structure Quality Assessment 


This is version 1.0 of the entry. See complete history


Literature

The Lab Oddity Prevails: Discovery of Pan-Cdk Inhibitor (R)- S-Cyclopropyl-S-(4-{[4-{[(1R,2R)-2-Hydroxy-1-Methylpropyl]Oxy}-5-(Trifluoromethyl)Pyrimidin-2-Yl]Amino}Phenyl)Sulfoximide (Bay 1000394) for the Treatment of Cancer.

Lucking, U.Jautelat, R.Kruger, M.Brumby, T.Lienau, P.Schafer, M.Briem, H.Schulze, J.Hillisch, A.Reichel, A.Wengner, A.M.Siemeister, G.

(2013) ChemMedChem 8: 1067

  • DOI: https://doi.org/10.1002/cmdc.201300096
  • Primary Citation of Related Structures:  
    4BGH

  • PubMed Abstract: 

    Lead optimization of a high-throughput screening hit led to the rapid identification of aminopyrimidine ZK 304709, a multitargeted CDK and VEGF-R inhibitor that displayed a promising preclinical profile. Nevertheless, ZK 304709 failed in phase I studies due to dose-limited absorption and high inter-patient variability, which was attributed to limited aqueous solubility and off-target activity against carbonic anhydrases. Further lead optimization efforts to address the off-target activity profile finally resulted in the introduction of a sulfoximine group, which is still a rather unusual approach in medicinal chemistry. However, the sulfoximine series of compounds quickly revealed very interesting properties, culminating in the identification of the nanomolar pan-CDK inhibitor BAY 1000394, which is currently being investigated in phase I clinical trials.


  • Organizational Affiliation

    Bayer Pharma AG, Global Drug Discovery, Medicinal Chemistry, 13353 Berlin, Germany. ulrich.luecking@bayer.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
CYCLIN-DEPENDENT KINASE 2298Homo sapiensMutation(s): 0 
EC: 2.7.11.22
UniProt & NIH Common Fund Data Resources
Find proteins for P24941 (Homo sapiens)
Explore P24941 
Go to UniProtKB:  P24941
PHAROS:  P24941
GTEx:  ENSG00000123374 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP24941
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
3I6
Query on 3I6

Download Ideal Coordinates CCD File 
B [auth A]4-((5-BROMO-4-(PROP-2-YN-1-YLAMINO)PYRIMIDIN-2-YL)AMINO)BENZENESULFONAMIDE
C13 H16 Br N5 O3 S
MJIALGDLOLWBRQ-MRVPVSSYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
3I6 PDBBind:  4BGH IC50: 4 (nM) from 1 assay(s)
Binding MOAD:  4BGH IC50: 4 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.246 
  • R-Value Work: 0.193 
  • R-Value Observed: 0.196 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 53.076α = 90
b = 71.795β = 90
c = 72.196γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
DENZOdata reduction
SCALEPACKdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-09-04
    Type: Initial release