2B54

Human cyclin dependent kinase 2 (CKD2)complexed with DIN-232305


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.85 Å
  • R-Value Free: 0.263 
  • R-Value Work: 0.158 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Synthesis and biological evaluation of 1-aryl-4,5-dihydro-1h-pyraxolo[3,4-d]pyrimidin-4-one inhibitors of cyclin dependent kinases

Markwalder, J.A.Arnone, M.R.Benfield, P.A.Boisclair, M.Burton, C.R.Chang, C.-C.Cox, S.S.Czerniak, P.M.Dean, C.L.Dolenaik, D.Grafstrom, R.Harrison, B.A.Kaltenbach III, R.F.Nugiel, D.A.Rossi, K.A.Sherk, S.R.Sisk, L.M.Stouten, P.Trainor, G.L.Worland, P.Seitz, S.P.

(2004) J Med Chem 47: 5894-5911

  • DOI: https://doi.org/10.1021/jm020455u
  • Primary Citation of Related Structures:  
    2B54

  • PubMed Abstract: 

    Using a high-throughput screening strategy, a series of 1-aryl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-4-ones was identified that inhibit the cyclin-dependent kinase (CDK) 4/cyclin D1 complex-mediated phosphorylation of a protein substrate with IC(50)s in the low micromolar range. On the basis of preliminary structure-activity relationships (SAR), a model was proposed in which these inhibitors occupy the ATP-binding site of the enzyme, forming critical hydrogen bonds to the same residue (Val96) to which the amino group in ATP is presumed to bind. X-ray diffraction studies on a later derivative bound to CDK2 support this binding mode. Iterative cycles of synthesis and screening lead to a novel series of potent, CDK2-selective 6-(arylmethyl)pyrazolopyrimidinones. Placement of a hydrogen-bond donor in the meta-position on the 6-arylmethyl group resulted in approximately 100-fold increases in CDK4 affinity, giving ligands that were equipotent inhibitors of CDK4 and CDK2. These compounds exhibit antiproliferative effects in the NCI HCT116 and other cell lines. The potency of these antiproliferative effects is enhanced in anilide derivatives and translates into tumor growth inhibition in a mouse xenograft model.


  • Organizational Affiliation

    Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000, USA. jay.markwalder@bms.com


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: 2.7.1.37
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
D05
Query on D05

Download Ideal Coordinates CCD File 
B [auth A]6-(3,4-DIHYDROXYBENZYL)-3-ETHYL-1-(2,4,6-TRICHLOROPHENYL)-1H-PYRAZOLO[3,4-D]PYRIMIDIN-4(5H)-ONE
C20 H15 Cl3 N4 O3
OPRAIFVPXXVXDL-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
D05 PDBBind:  2B54 IC50: 20 (nM) from 1 assay(s)
BindingDB:  2B54 IC50: 20 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.85 Å
  • R-Value Free: 0.263 
  • R-Value Work: 0.158 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 72.97α = 90
b = 73.16β = 90
c = 54.26γ = 90
Software Package:
Software NamePurpose
PROCESSdata collection
SCALEdata reduction
X-PLORmodel building
CNXrefinement
PROCESSdata reduction
SCALEdata scaling
X-PLORphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

  • Released Date: 2005-10-11 
  • Deposition Author(s): Chang, C.-C.

Revision History  (Full details and data files)

  • Version 1.0: 2005-10-11
    Type: Initial release
  • Version 1.1: 2008-05-01
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2024-02-14
    Changes: Data collection, Database references, Derived calculations