4LYN

Crystal structure of cyclin-dependent kinase 2 (cdk2-wt) complex with (2s)-n-(5-(((5-tert-butyl-1,3-oxazol-2-yl)methyl)sulfanyl)-1,3-thiazol-2-yl)-2-phenylpropanamide


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.238 
  • R-Value Work: 0.185 
  • R-Value Observed: 0.187 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Discovery of Aminothiazole Inhibitors of Cyclin-Dependent Kinase 2: Synthesis, X-Ray Crystallographic Analysis, and Biological Activities

Kim, K.S.Kimball, S.D.Misra, R.N.Rawlins, D.B.Hunt, J.T.Xiao, H.-Y.Lu, S.Qian, L.Han, W.C.Shan, W.Mitt, T.Cai, Z.-W.Poss, M.A.Zhu, H.Sack, J.S.Tokarski, J.S.Chang, C.Y.Pavletich, N.Kamath, A.Humphreys, W.G.Marathe, P.Bursuker, I.Kellar, K.A.Roongta, U.Batorsky, R.Mulheron, J.G.Bol, D.Fairchild, C.R.Lee, F.Y.Webster, K.R.

(2002) J Med Chem 45: 3905-3927

  • DOI: https://doi.org/10.1021/jm0201520
  • Primary Citation of Related Structures:  
    4LYN

  • PubMed Abstract: 

    High throughput screening identified 2-acetamido-thiazolylthio acetic ester 1 as an inhibitor of cyclin-dependent kinase 2 (CDK2). Because this compound is inactive in cells and unstable in plasma, we have stabilized it to metabolic hydrolysis by replacing the ester moiety with a 5-ethyl-substituted oxazole as in compound 14. Combinatorial and parallel synthesis provided a rapid analysis of the structure-activity relationship (SAR) for these inhibitors of CDK2, and over 100 analogues with IC(50) values in the 1-10 nM range were rapidly prepared. The X-ray crystallographic data of the inhibitors bound to the active site of CDK2 protein provided insight into the binding modes of these inhibitors, and the SAR of this series of analogues was rationalized. Many of these analogues displayed potent and broad spectrum antiproliferative activity across a panel of tumor cell lines in vitro. In addition, A2780 ovarian carcinoma cells undergo rapid apoptosis following exposure to CDK2 inhibitors of this class. Mechanism of action studies have confirmed that the phosphorylation of CDK2 substrates such as RB, histone H1, and DNA polymerase alpha (p70 subunit) is reduced in the presence of compound 14. Further optimization led to compounds such as water soluble 45, which possesses a favorable pharmacokinetic profile in mice and demonstrates significant antitumor activity in vivo in several murine and human models, including an engineered murine mammary tumor that overexpresses cyclin E, the coactivator of CDK2.


  • Organizational Affiliation

    Department of Oncology Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000, USA. kyoung.kim@bms.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Cyclin-dependent kinase 2298Homo sapiensMutation(s): 0 
Gene Names: CDK2CDKN2
EC: 2.7.11.22
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
1YG
Query on 1YG

Download Ideal Coordinates CCD File 
B [auth A](2S)-N-(5-{[(5-tert-butyl-1,3-oxazol-2-yl)methyl]sulfanyl}-1,3-thiazol-2-yl)-2-phenylpropanamide
C20 H23 N3 O2 S2
FIZSPBCJAWUURL-ZDUSSCGKSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
1YG PDBBind:  4LYN IC50: 60 (nM) from 1 assay(s)
BindingDB:  4LYN IC50: 60 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.238 
  • R-Value Work: 0.185 
  • R-Value Observed: 0.187 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 53.46α = 90
b = 71.84β = 90
c = 72.19γ = 90
Software Package:
Software NamePurpose
AMoREphasing
BUSTERrefinement
X-GENdata reduction
X-GENdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2013-10-02 
  • Deposition Author(s): Sack, J.S.

Revision History  (Full details and data files)

  • Version 1.0: 2013-10-02
    Type: Initial release
  • Version 1.1: 2017-11-15
    Changes: Refinement description
  • Version 1.2: 2018-01-24
    Changes: Database references
  • Version 1.3: 2024-02-28
    Changes: Data collection, Database references, Derived calculations