4CFX

Structure-based design of C8-substituted O6-cyclohexylmethoxyguanine CDK1 and 2 inhibitors.


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.50 Å
  • R-Value Free: 0.269 
  • R-Value Work: 0.204 
  • R-Value Observed: 0.207 

wwPDB Validation   3D Report Full Report


This is version 1.1 of the entry. See complete history


Literature

8-Substituted O6-Cyclohexylmethylguanine Cdk2 Inhibitors; Using Structure-Based Inhibitor Design to Optimise an Alternative Binding Mode.

Carbain, B.Paterson, D.J.Anscombe, E.Campbell-Dexter, A.Cano, C.Echalier, A.Endicott, J.Golding, B.T.Haggerty, K.Hardcastle, I.R.Jewsbury, P.J.Newell, D.R.Noble, M.Roche, C.Wang, L.Griffin, R.J.

(2014) J Med Chem 57: 56

  • DOI: https://doi.org/10.1021/jm401555v
  • Primary Citation of Related Structures:  
    1W8C, 4CFM, 4CFN, 4CFU, 4CFV, 4CFW, 4CFX

  • PubMed Abstract: 

    Evaluation of the effects of purine C-8 substitution within a series of CDK1/2-selective O(6)-cyclohexylmethylguanine derivatives revealed that potency decreases initially with increasing size of the alkyl substituent. Structural analysis showed that C-8 substitution is poorly tolerated, and to avoid unacceptable steric interactions, these compounds adopt novel binding modes. Thus, 2-amino-6-cyclohexylmethoxy-8-isopropyl-9H-purine adopts a "reverse" binding mode where the purine backbone has flipped 180°. This provided a novel lead chemotype from which we have designed more potent CDK2 inhibitors using, in the first instance, quantum mechanical energy calculations. Introduction of an ortho-tolyl or ortho-chlorophenyl group at the purine C-8 position restored the potency of these "reverse" binding mode inhibitors to that of the parent 2-amino-6-cyclohexylmethoxy-9H-purine. By contrast, the corresponding 8-(2-methyl-3-sulfamoylphenyl)-purine derivative exhibited submicromolar CDK2-inhibitory activity by virtue of engineered additional interactions with Asp86 and Lys89 in the reversed binding mode, as confirmed by X-ray crystallography.


  • Organizational Affiliation

    Department of Biochemistry, University of Oxford , South Parks Road, Oxford OX1 3QU, U.K.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
CYCLIN-DEPENDENT KINASE 2
A, C
303Homo sapiensMutation(s): 0 
EC: 2.7.11.22 (PDB Primary Data), 2.7.11.23 (PDB Primary Data)
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
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  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
CYCLIN-A2
B, D
260Homo sapiensMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for P20248 (Homo sapiens)
Explore P20248 
Go to UniProtKB:  P20248
PHAROS:  P20248
GTEx:  ENSG00000145386 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP20248
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
G6T
Query on G6T

Download Ideal Coordinates CCD File 
E [auth A],
F [auth C]
3-[2-amino-6-(cyclohexylmethoxy)-7H-purin-8-yl]benzenesulfonamide
C18 H22 N6 O3 S
XNHSEOXNPOIZSH-UHFFFAOYSA-N
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
TPO
Query on TPO
A, C
L-PEPTIDE LINKINGC4 H10 N O6 PTHR
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.50 Å
  • R-Value Free: 0.269 
  • R-Value Work: 0.204 
  • R-Value Observed: 0.207 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 74.66α = 90
b = 136.56β = 90
c = 149.03γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2014-12-10
    Type: Initial release
  • Version 1.1: 2023-12-20
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description