PDBsum entry 2w1h

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Transferase PDB id
Protein chain
283 a.a. *
Waters ×221
* Residue conservation analysis
PDB id:
Name: Transferase
Title: Fragment-based discovery of the pyrazol-4-yl urea (at9283), a multi-targeted kinase inhibitor with potent aurora kinase activity
Structure: Cell division protein kinase 2. Chain: a. Synonym: p33 protein kinase, cdk2. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9.
2.15Å     R-factor:   0.263     R-free:   0.308
Authors: S.Howard,V.Berdini,J.A.Boulstridge,M.G.Carr,D.M.Cross, J.Curry,L.A.Devine,T.R.Early,L.Fazal,A.L.Gill,M.Heathcote, S.Maman,J.E.Matthews,R.L.Mcmenamin,E.F.Navarro,M.A.O'Brien, M.O'Reilly,D.C.Rees,M.Reule,D.Tisi,G.Williams,M.Vinkovic, P.G.Wyatt
Key ref: S.Howard et al. (2009). Fragment-based discovery of the pyrazol-4-yl urea (AT9283), a multitargeted kinase inhibitor with potent aurora kinase activity. J Med Chem, 52, 379-388. PubMed id: 19143567 DOI: 10.1021/jm800984v
17-Oct-08     Release date:   27-Jan-09    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P24941  (CDK2_HUMAN) -  Cyclin-dependent kinase 2
298 a.a.
283 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.  - Cyclin-dependent kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a protein = ADP + a phosphoprotein
+ protein
+ phosphoprotein
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     cyclin-dependent protein kinase holoenzyme complex   15 terms 
  Biological process     regulation of gene silencing   28 terms 
  Biochemical function     nucleotide binding     12 terms  


DOI no: 10.1021/jm800984v J Med Chem 52:379-388 (2009)
PubMed id: 19143567  
Fragment-based discovery of the pyrazol-4-yl urea (AT9283), a multitargeted kinase inhibitor with potent aurora kinase activity.
S.Howard, V.Berdini, J.A.Boulstridge, M.G.Carr, D.M.Cross, J.Curry, L.A.Devine, T.R.Early, L.Fazal, A.L.Gill, M.Heathcote, S.Maman, J.E.Matthews, R.L.McMenamin, E.F.Navarro, M.A.O'Brien, M.O'Reilly, D.C.Rees, M.Reule, D.Tisi, G.Williams, M.Vinković, P.G.Wyatt.
Here, we describe the identification of a clinical candidate via structure-based optimization of a ligand efficient pyrazole-benzimidazole fragment. Aurora kinases play a key role in the regulation of mitosis and in recent years have become attractive targets for the treatment of cancer. X-ray crystallographic structures were generated using a novel soakable form of Aurora A and were used to drive the optimization toward potent (IC(50) approximately 3 nM) dual Aurora A/Aurora B inhibitors. These compounds inhibited growth and survival of HCT116 cells and produced the polyploid cellular phenotype typically associated with Aurora B kinase inhibition. Optimization of cellular activity and physicochemical properties ultimately led to the identification of compound 16 (AT9283). In addition to Aurora A and Aurora B, compound 16 was also found to inhibit a number of other kinases including JAK2 and Abl (T315I). This compound demonstrated in vivo efficacy in mouse xenograft models and is currently under evaluation in phase I clinical trials.

Literature references that cite this PDB file's key reference

  PubMed id Reference
21147253 A.Yan, L.Wang, S.Xu, and J.Xu (2011).
Aurora-A kinase inhibitor scaffolds and binding modes.
  Drug Discov Today, 16, 260-269.  
21421314 A.Yan, Y.Chong, L.Wang, X.Hu, and K.Wang (2011).
Prediction of biological activity of Aurora-A kinase inhibitors by multilinear regression analysis and support vector machine.
  Bioorg Med Chem Lett, 21, 2238-2243.  
21102425 D.Bixby, and M.Talpaz (2011).
Seeking the causes and solutions to imatinib-resistance in chronic myeloid leukemia.
  Leukemia, 25, 7.  
21327563 F.P.Santos, and A.Quintás-Cardama (2011).
New drugs for chronic myelogenous leukemia.
  Curr Hematol Malig Rep, 6, 96.  
21323612 J.Lee, S.M.Paek, and S.Y.Han (2011).
FMS-like tyrosine kinase 3 inhibitors: a patent review.
  Expert Opin Ther Pat, 21, 483-503.  
21959288 P.D.Leeson, and S.A.St-Gallay (2011).
The influence of the 'organizational factor' on compound quality in drug discovery.
  Nat Rev Drug Discov, 10, 749-765.  
20673774 R.E.Hubbard (2011).
Structure-based drug discovery and protein targets in the CNS.
  Neuropharmacology, 60, 7.  
19714578 S.Schenone, O.Bruno, M.Radi, and M.Botta (2011).
New insights into small-molecule inhibitors of Bcr-Abl.
  Med Res Rev, 31, 1.  
21222017 Y.Cheng, W.Cui, Q.Chen, C.H.Tung, M.Ji, and F.Zhang (2011).
The molecular mechanism studies of chirality effect of PHA-739358 on Aurora kinase A by molecular dynamics simulation and free energy calculations.
  J Comput Aided Mol Des, 25, 171-180.  
20067443 C.A.Dodson, M.Kosmopoulou, M.W.Richards, B.Atrash, V.Bavetsias, J.Blagg, and R.Bayliss (2010).
Crystal structure of an Aurora-A mutant that mimics Aurora-B bound to MLN8054: insights into selectivity and drug design.
  Biochem J, 427, 19-28.
PDB codes: 2wtv 2wtw
20471246 C.W.Murray, and T.L.Blundell (2010).
Structural biology in fragment-based drug design.
  Curr Opin Struct Biol, 20, 497-507.  
20922218 E.J.Ashforth, C.Fu, X.Liu, H.Dai, F.Song, H.Guo, and L.Zhang (2010).
Bioprospecting for antituberculosis leads from microbial metabolites.
  Nat Prod Rep, 27, 1709-1719.  
21040493 J.Qin, L.Xi, J.Du, H.Liu, and X.Yao (2010).
QSAR studies on aminothiazole derivatives as aurora a kinase inhibitors.
  Chem Biol Drug Des, 76, 527-537.  
  20634968 K.L.Whalen, K.L.Pankow, S.R.Blanke, and M.A.Spies (2010).
Exploiting Enzyme Plasticity in Virtual Screening: High Efficiency Inhibitors of Glutamate Racemase.
  ACS Med Chem Lett, 1, 9.  
20039358 M.S.Coumar, M.T.Tsai, C.Y.Chu, B.J.Uang, W.H.Lin, C.Y.Chang, T.Y.Chang, J.S.Leou, C.H.Teng, J.S.Wu, M.Y.Fang, C.H.Chen, J.T.Hsu, S.Y.Wu, Y.S.Chao, and H.P.Hsieh (2010).
Identification, SAR studies, and X-ray co-crystallographic analysis of a novel furanopyrimidine aurora kinase A inhibitor.
  ChemMedChem, 5, 255-267.
PDB code: 3k5u
20548094 R.Tanaka, M.S.Squires, S.Kimura, A.Yokota, R.Nagao, T.Yamauchi, M.Takeuchi, H.Yao, M.Reule, T.Smyth, J.F.Lyons, N.T.Thompson, E.Ashihara, O.G.Ottmann, and T.Maekawa (2010).
Activity of the multitargeted kinase inhibitor, AT9283, in imatinib-resistant BCR-ABL-positive leukemic cells.
  Blood, 116, 2089-2095.  
19359241 P.J.Scutt, M.L.Chu, D.A.Sloane, M.Cherry, C.R.Bignell, D.H.Williams, and P.A.Eyers (2009).
Discovery and exploitation of inhibitor-resistant aurora and polo kinase mutants for the analysis of mitotic networks.
  J Biol Chem, 284, 15880-15893.  
19568282 S.Lapenna, and A.Giordano (2009).
Cell cycle kinases as therapeutic targets for cancer.
  Nat Rev Drug Discov, 8, 547-566.  
18991785 X.Tao, H.S.Chon, S.Fu, J.J.Kavanagh, and W.Hu (2008).
Update on aurora kinase inhibitors in gynecologic malignancies.
  Recent Pat Anticancer Drug Discov, 3, 162-177.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.