2VU3

Identification of N-(4-piperidinyl)-4-(2,6-dichlorobenzoylamino)-1H- pyrazole-3-carboxamide (AT7519), a Novel Cyclin Dependent Kinase Inhibitor Using Fragment-Based X-Ray Crystallography and Structure Based Drug Design.


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.85 Å
  • R-Value Free: 0.246 
  • R-Value Work: 0.202 
  • R-Value Observed: 0.205 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Identification of N-(4-Piperidinyl)-4-(2,6-Dichlorobenzoylamino)-1H-Pyrazole-3-Carboxamide (at7519), a Novel Cyclin Dependent Kinase Inhibitor Using Fragment-Based X-Ray Crystallography and Structure Based Drug Design.

Wyatt, P.G.Woodhead, A.J.Berdini, V.Boulstridge, J.A.Carr, M.G.Cross, D.M.Davis, D.J.Devine, L.A.Early, T.R.Feltell, R.E.Lewis, E.J.Mcmenamin, R.L.Navarro, E.F.O'Brien, M.A.O'Reilly, M.Reule, M.Saxty, G.Seavers, L.C.A.Smith, D.Squires, M.S.Trewartha, G.Walker, M.T.Woolford, A.J.

(2008) J Med Chem 51: 4986

  • DOI: https://doi.org/10.1021/jm800382h
  • Primary Citation of Related Structures:  
    2VTA, 2VTH, 2VTI, 2VTJ, 2VTL, 2VTM, 2VTN, 2VTO, 2VTP, 2VTQ, 2VTR, 2VTS, 2VTT, 2VU3

  • PubMed Abstract: 

    The application of fragment-based screening techniques to cyclin dependent kinase 2 (CDK2) identified multiple (>30) efficient, synthetically tractable small molecule hits for further optimization. Structure-based design approaches led to the identification of multiple lead series, which retained the key interactions of the initial binding fragments and additionally explored other areas of the ATP binding site. The majority of this paper details the structure-guided optimization of indazole (6) using information gained from multiple ligand-CDK2 cocrystal structures. Identification of key binding features for this class of compounds resulted in a series of molecules with low nM affinity for CDK2. Optimisation of cellular activity and characterization of pharmacokinetic properties led to the identification of 33 (AT7519), which is currently being evaluated in clinical trials for the treatment of human cancers.


  • Organizational Affiliation

    Astex Therapeutics Ltd, 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, United Kingdom. p.g.wyatt@dundee.ac.uk


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
CELL DIVISION PROTEIN KINASE 2298Homo sapiensMutation(s): 0 
EC: 2.7.11.1 (PDB Primary Data), 2.7.11.22 (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
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
LZE
Query on LZE

Download Ideal Coordinates CCD File 
B [auth A]4-{[(2,6-dichlorophenyl)carbonyl]amino}-N-piperidin-4-yl-1H-pyrazole-3-carboxamide
C16 H17 Cl2 N5 O2
OVPNQJVDAFNBDN-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
LZE BindingDB:  2VU3 Ki: min: 44, max: 510 (nM) from 2 assay(s)
Kd: 30 (nM) from 1 assay(s)
IC50: min: 32, max: 47 (nM) from 2 assay(s)
Binding MOAD:  2VU3 IC50: 47 (nM) from 1 assay(s)
PDBBind:  2VU3 IC50: 47 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.85 Å
  • R-Value Free: 0.246 
  • R-Value Work: 0.202 
  • R-Value Observed: 0.205 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 53.681α = 90
b = 71.516β = 90
c = 72.048γ = 90
Software Package:
Software NamePurpose
BUSTER-TNTrefinement
CrystalCleardata reduction
CrystalCleardata scaling
AMoREphasing

Structure Validation

View Full Validation Report



Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2008-08-05
    Type: Initial release
  • Version 1.1: 2011-05-08
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2017-06-28
    Changes: Data collection