2FVD

Cyclin Dependent Kinase 2 (CDK2) with diaminopyrimidine inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.85 Å
  • R-Value Free: 0.235 
  • R-Value Work: 0.207 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Discovery of [4-Amino-2-(1-methanesulfonylpiperidin-4-ylamino)pyrimidin-5-yl](2,3-difluoro-6- methoxyphenyl)methanone (R547), a potent and selective cyclin-dependent kinase inhibitor with significant in vivo antitumor activity.

Chu, X.J.DePinto, W.Bartkovitz, D.So, S.S.Vu, B.T.Packman, K.Lukacs, C.Ding, Q.Jiang, N.Wang, K.Goelzer, P.Yin, X.Smith, M.A.Higgins, B.X.Chen, Y.Xiang, Q.Moliterni, J.Kaplan, G.Graves, B.Lovey, A.Fotouhi, N.

(2006) J Med Chem 49: 6549-6560

  • DOI: https://doi.org/10.1021/jm0606138
  • Primary Citation of Related Structures:  
    2FVD

  • PubMed Abstract: 

    The cyclin-dependent kinases (CDKs) and their cyclin partners are key regulators of the cell cycle. Since deregulation of CDKs is found with high frequency in many human cancer cells, pharmacological inhibition of CDKs with small molecules has the potential to provide an effective strategy for the treatment of cancer. The 2,4-diamino-5-ketopyrimidines 6 reported here represent a novel class of potent and ATP-competitive inhibitors that selectively target the cyclin-dependent kinase family. This diaminopyrimidine core with a substituted 4-piperidine moiety on the C2-amino position and 2-methoxybenzoyl at the C5 position has been identified as the critical structure responsible for the CDK inhibitory activity. Further optimization has led to a good number of analogues that show potent inhibitory activities against CDK1, CDK2, and CDK4 but are inactive against a large panel of serine/threonine and tyrosine kinases (K(i) > 10 microM). As one of these representative analogues, compound 39 (R547) has the best CDK inhibitory activities (K(i) = 0.001, 0.003, and 0.001 microM for CDK1, CDK2, and CDK4, respectively) and excellent in vitro cellular potency, inhibiting the growth of various human tumor cell lines including an HCT116 cell line (IC(50) = 0.08 microM). An X-ray crystal structure of 39 bound to CDK2 has been determined in this study, revealing a binding mode that is consistent with our SAR. Compound 39 demonstrates significant in vivo efficacy in the HCT116 human colorectal tumor xenograft model in nude mice with up to 95% tumor growth inhibition. On the basis of its superior overall profile, 39 was chosen for further evaluation and has progressed into Phase I clinical trial for the treatment of cancer.


  • Organizational Affiliation

    Department of Discovery Chemistry, Discovery Oncology, Non-Clinical Drug Safety and Discovery Technologies, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, USA. xin-jie.chu@roche.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 
Gene Names: CDK2
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
LIA
Query on LIA

Download Ideal Coordinates CCD File 
B [auth A](4-AMINO-2-{[1-(METHYLSULFONYL)PIPERIDIN-4-YL]AMINO}PYRIMIDIN-5-YL)(2,3-DIFLUORO-6-METHOXYPHENYL)METHANONE
C18 H21 F2 N5 O4 S
JRNJNYBQQYBCLE-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
LIA BindingDB:  2FVD Ki: 3 (nM) from 1 assay(s)
Kd: 0.53 (nM) from 1 assay(s)
PDBBind:  2FVD Ki: 3 (nM) from 1 assay(s)
Binding MOAD:  2FVD Ki: 3 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.85 Å
  • R-Value Free: 0.235 
  • R-Value Work: 0.207 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 53.506α = 90
b = 71.647β = 90
c = 71.692γ = 90
Software Package:
Software NamePurpose
CNXrefinement
HKL-2000data reduction
SCALEPACKdata scaling
CNXphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2006-10-10
    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