5M57

Nek2 bound to arylaminopurine 6


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.274 
  • R-Value Work: 0.219 
  • R-Value Observed: 0.221 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Structure-guided design of purine-based probes for selective Nek2 inhibition.

Coxon, C.R.Wong, C.Bayliss, R.Boxall, K.Carr, K.H.Fry, A.M.Hardcastle, I.R.Matheson, C.J.Newell, D.R.Sivaprakasam, M.Thomas, H.Turner, D.Yeoh, S.Wang, L.Z.Griffin, R.J.Golding, B.T.Cano, C.

(2017) Oncotarget 8: 19089-19124

  • DOI: https://doi.org/10.18632/oncotarget.13249
  • Primary Citation of Related Structures:  
    5M51, 5M53, 5M55, 5M57

  • PubMed Abstract: 

    Nek2 (NIMA-related kinase 2) is a cell cycle-dependent serine/threonine protein kinase that regulates centrosome separation at the onset of mitosis. Overexpression of Nek2 is common in human cancers and suppression can restrict tumor cell growth and promote apoptosis. Nek2 inhibition with small molecules, therefore, offers the prospect of a new therapy for cancer. To achieve this goal, a better understanding of the requirements for selective-inhibition of Nek2 is required. 6-Alkoxypurines were identified as ATP-competitive inhibitors of Nek2 and CDK2. Comparison with CDK2-inhibitor structures indicated that judicious modification of the 6-alkoxy and 2-arylamino substituents could achieve discrimination between Nek2 and CDK2. In this study, a library of 6-cyclohexylmethoxy-2-arylaminopurines bearing carboxamide, sulfonamide and urea substituents on the 2-arylamino ring was synthesized. Few of these compounds were selective for Nek2 over CDK2, with the best result being obtained for 3-((6-(cyclohexylmethoxy)-9H-purin-2-yl)amino)-N,N-dimethylbenzamide (CDK2 IC50 = 7.0 μM; Nek2 IC50 = 0.62 μM) with >10-fold selectivity. Deletion of the 6-substituent abrogated activity against both Nek2 and CDK2. Nine compounds containing an (E)-dialkylaminovinyl substituent at C-6, all showed selectivity for Nek2, e.g. (E)-6-(2-(azepan-1-yl)vinyl)-N-phenyl-9H-purin-2-amine (CDK2 IC50 = 2.70 μM; Nek2 IC50 = 0.27 μM). Structural biology of selected compounds enabled a partial rationalization of the observed structure activity relationships and mechanism of Nek2 activation. This showed that carboxamide 11 is the first reported inhibitor of Nek2 in the DFG-in conformation.


  • Organizational Affiliation

    Northern Institute for Cancer Research, School of Chemistry, Newcastle University, Newcastle upon Tyne, UK.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Serine/threonine-protein kinase Nek2279Homo sapiensMutation(s): 0 
Gene Names: NEK2NEK2ANLK1
EC: 2.7.11.1
UniProt & NIH Common Fund Data Resources
Find proteins for P51955 (Homo sapiens)
Explore P51955 
Go to UniProtKB:  P51955
PHAROS:  P51955
GTEx:  ENSG00000117650 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP51955
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
4SP
Query on 4SP

Download Ideal Coordinates CCD File 
B [auth A]O6-CYCLOHEXYLMETHOXY-2-(4'-SULPHAMOYLANILINO) PURINE
C18 H22 N6 O3 S
OWXORKPNCHJYOF-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
4SP Binding MOAD:  5M57 IC50: 1.20e+4 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.274 
  • R-Value Work: 0.219 
  • R-Value Observed: 0.221 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 56.733α = 90
b = 73.595β = 90
c = 75.393γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2016-11-23 
  • Deposition Author(s): Bayliss, R.

Revision History  (Full details and data files)

  • Version 1.0: 2016-11-23
    Type: Initial release
  • Version 1.1: 2017-05-03
    Changes: Database references
  • Version 1.2: 2024-01-17
    Changes: Data collection, Database references, Refinement description