2BPM

STRUCTURE OF CDK2-CYCLIN A WITH PHA-630529


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.271 
  • R-Value Work: 0.229 

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Ligand Structure Quality Assessment 


This is version 1.5 of the entry. See complete history


Literature

3-Aminopyrazole Inhibitors of Cdk2-Cyclin a as Antitumor Agents. 2. Lead Optimization

Pevarello, P.Brasca, M.G.Orsini, P.Traquandi, G.Longo, A.Nesi, M.Orzi, F.Piutti, C.Sansonna, P.Varasi, M.Cameron, A.Vulpetti, A.Roletto, F.Alzani, R.Ciomei, M.Albanese, C.Pastori, W.Marsiglio, A.Pesenti, E.Fiorentini, F.Bischoff, J.R.Mercurio, C.

(2005) J Med Chem 48: 2944

  • DOI: https://doi.org/10.1021/jm0408870
  • Primary Citation of Related Structures:  
    2BPM

  • PubMed Abstract: 

    Inhibitors of cyclin-dependent kinases (CDK) such as CDK2/cyclin A-E are currently undergoing clinical trials to verify their potential as new anticancer agents. In a previous article we described the lead discovery process of a 3-aminopyrazole class of CDK2/cyclin A-E inhibitors. The endpoint of this process was PNU-292137, a compound endowed with in vivo antitumor activity in a mouse tumor xenograft model. We optimized this lead compound to improve some physicochemical properties, notably solubility and plasma protein binding. This lead optimization process brought us to the discovery of (2S)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-[4-(2-oxo-1-pyrrolidinyl)phenyl]propanamide (PHA-533533, 13), a compound with a balanced activity vs druglike profile. Compound 13 inhibited CDK2/cyclin A with a K(i) of 31 nM, counteracting tumor cell proliferation of different cell lines with an IC(50) in the submicromolar range. Solubility was improved more than 10 times over the starting lead, while plasma protein binding was decreased from 99% to 74%. With exploitation of this globally enhanced in vitro profile, 13 was more active than PNU-292137 in vivo in the A2780 xenograft model showing a tumor growth inhibition of 70%. Proof of mechanism of action was obtained in vivo by immunohistochemical analysis of tumor slices of 13-treated vs untreated animals.


  • Organizational Affiliation

    Department Chemistry, Nerviano Medical Sciences, BU-Oncology and BU-Preclinical Science, Viale Pasteur 10, 20014 Nerviano (MI), Italy. paolo.pevarello@nervianoms.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
CELL DIVISION PROTEIN KINASE 2
A, C
309Homo 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
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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
265Homo 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
Binding Affinity Annotations 
IDSourceBinding Affinity
529 PDBBind:  2BPM IC50: 2 (nM) from 1 assay(s)
Binding MOAD:  2BPM IC50: 2 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.271 
  • R-Value Work: 0.229 
  • Space Group: P 62 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 183.614α = 90
b = 183.614β = 90
c = 214.129γ = 120
Software Package:
Software NamePurpose
CNXrefinement
DENZOdata reduction
SCALEPACKdata scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2005-12-08
    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: 2019-04-03
    Changes: Data collection, Other, Source and taxonomy
  • Version 1.4: 2019-10-16
    Changes: Data collection, Other
  • Version 1.5: 2023-12-13
    Changes: Data collection, Database references, Refinement description