5D1J

CRYSTAL STRUCTURE OF CYCLIN-DEPENDENT KINASE 2 (CDK2-WT) COMPLEX WITH N-[5-[[[5-(1,1-DIMETHYLETHYL)-2-OXAZOLYL] METHYL]THIO]-2-THIAZOLYL]-4-PIPERIDINECARBOXAMIDE (BMS-387032)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.232 
  • R-Value Work: 0.201 
  • R-Value Observed: 0.203 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

N-(Cycloalkylamino)Acyl-2-Aminothiazole Inhibitors Of Cyclin-Dependent Kinase 2. N-[5-[[[5-(1,1-Dimethylethyl) -2-Oxazolyl]Methyl]Thio]-2-Thiazolyl]-4-Piperidinecarboxamide (Bms-387032), A Highly Efficacious And Selective Antitumor Agent

Misra, R.N.Xiao, H.Y.Kim, K.S.Lu, S.Han, W.C.Barbosa, S.A.Hunt, J.T.Rawlins, D.B.Shan, W.Ahmed, S.Z.Qian, L.Chen, B.C.Zhao, R.Bednarz, M.S.Kellar, K.A.Mulheron, J.G.Batorsky, R.Roongta, U.Kamath, A.Marathe, P.Ranadive, S.A.Sack, J.S.Tokarski, J.S.Pavletich, N.P.Lee, F.Y.F.Webster, K.R.Kimball, S.D.

(2004) J Med Chem 47: 1719

  • DOI: https://doi.org/10.1021/jm0305568
  • Primary Citation of Related Structures:  
    5D1J

  • PubMed Abstract: 

    N-Acyl-2-aminothiazoles with nonaromatic acyl side chains containing a basic amine were found to be potent, selective inhibitors of CDK2/cycE which exhibit antitumor activity in mice. In particular, compound 21 [N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide, BMS-387032], has been identified as an ATP-competitive and CDK2-selective inhibitor which has been selected to enter Phase 1 human clinical trials as an antitumor agent. In a cell-free enzyme assay, 21 showed a CDK2/cycE IC(50) = 48 nM and was 10- and 20-fold selective over CDK1/cycB and CDK4/cycD, respectively. It was also highly selective over a panel of 12 unrelated kinases. Antiproliferative activity was established in an A2780 cellular cytotoxicity assay in which 21 showed an IC(50) = 95 nM. Metabolism and pharmacokinetic studies showed that 21 exhibited a plasma half-life of 5-7 h in three species and moderately low protein binding in both mouse (69%) and human (63%) serum. Dosed orally to mouse, rat, and dog, 21 showed 100%, 31%, and 28% bioavailability, respectively. As an antitumor agent in mice, 21 administered at its maximum-tolerated dose exhibited a clearly superior efficacy profile when compared to flavopiridol in both an ip/ip P388 murine tumor model and in a s.c./i.p. A2780 human ovarian carcinoma xenograft model.


  • Organizational Affiliation

    Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 4000, Princeton, New Jersey 08543-4000, USA. raj_n_misra@hotmail.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
56H
Query on 56H

Download Ideal Coordinates CCD File 
B [auth A]N-(5-{[(5-tert-butyl-1,3-oxazol-2-yl)methyl]sulfanyl}-1,3-thiazol-2-yl)piperidine-4-carboxamide
C17 H24 N4 O2 S2
OUSFTKFNBAZUKL-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
56H BindingDB:  5D1J Ki: 38 (nM) from 1 assay(s)
Kd: 69 (nM) from 1 assay(s)
IC50: min: 38, max: 52 (nM) from 4 assay(s)
Binding MOAD:  5D1J IC50: 48 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.232 
  • R-Value Work: 0.201 
  • R-Value Observed: 0.203 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 53.724α = 90
b = 72.778β = 90
c = 72.535γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
BUSTERrefinement
AMoREphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2015-08-12 
  • Deposition Author(s): Sack, J.S.

Revision History  (Full details and data files)

  • Version 1.0: 2015-08-12
    Type: Initial release
  • Version 1.1: 2017-11-22
    Changes: Derived calculations, Refinement description
  • Version 1.2: 2024-03-06
    Changes: Data collection, Database references