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PDBsum entry 2j4z
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protein ligands Protein-protein interface(s) links
Transferase PDB id
2j4z

 

 

 

 

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Contents
Protein chains
264 a.a. *
Ligands
626 ×2
ARS ×3
Waters ×194
* Residue conservation analysis
PDB id:
2j4z
Name: Transferase
Title: Structure of aurora-2 in complex with pha-680626
Structure: Serine threonine-protein kinase 6. Chain: a, b. Fragment: catalytic domain, residues 100-403. Synonym: serine/threonine kinase 15, aurora/ipl1-related kinase 1, aurora-related kinase 1, hark1, aurora-a, breast-tumor-amplified kinase. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: high five.
Resolution:
2.00Å     R-factor:   0.214     R-free:   0.249
Authors: A.D.Cameron,G.Izzo,P.Storici,L.Rusconi,D.Fancelli,M.Varasi,D.Berta, S.Bindi,B.Forte,D.Severino,R.Tonani,P.Vianello
Key ref: D.Fancelli et al. (2006). 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazoles: identification of a potent Aurora kinase inhibitor with a favorable antitumor kinase inhibition profile. J Med Chem, 49, 7247-7251. PubMed id: 17125279 DOI: 10.1021/jm060897w
Date:
08-Sep-06     Release date:   06-Nov-06    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
O14965  (AURKA_HUMAN) -  Aurora kinase A from Homo sapiens
Seq:
Struc: 		403 a.a.
264 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.2.7.11.1  - non-specific serine/threonine protein kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction:
1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H+
2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H+
L-seryl-[protein]
 + ATP
 = O-phospho-L-seryl-[protein]
 + ADP
 + H(+)
L-threonyl-[protein]
 + ATP
 = O-phospho-L-threonyl-[protein]
 + ADP
 + H(+)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 

 
    reference    
 
 
DOI no: 10.1021/jm060897w J Med Chem 49:7247-7251 (2006)
PubMed id: 17125279  
 
 
1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazoles: identification of a potent Aurora kinase inhibitor with a favorable antitumor kinase inhibition profile.
D.Fancelli, J.Moll, M.Varasi, R.Bravo, R.Artico, D.Berta, S.Bindi, A.Cameron, I.Candiani, P.Cappella, P.Carpinelli, W.Croci, B.Forte, M.L.Giorgini, J.Klapwijk, A.Marsiglio, E.Pesenti, M.Rocchetti, F.Roletto, D.Severino, C.Soncini, P.Storici, R.Tonani, P.Zugnoni, P.Vianello.
 
  ABSTRACT  
 
The optimization of a series of 5-phenylacetyl 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole derivatives toward the inhibition of Aurora kinases led to the identification of compound 9d. This is a potent inhibitor of Aurora kinases that also shows low nanomolar potency against additional anticancer kinase targets. Based on its high antiproliferative activity on different cancer cell lines, favorable chemico-physical and pharmacokinetic properties, and high efficacy in in vivo tumor models, compound 9d was ultimately selected for further development.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21352071 A.C.Burke, R.T.Swords, K.Kelly, and F.J.Giles (2011).
Current status of agents active against the T315I chronic myeloid leukemia phenotype.
  Expert Opin Emerg Drugs, 16, 85.  
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.  
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.  
20147976 A.S.Moore, J.Blagg, S.Linardopoulos, and A.D.Pearson (2010).
Aurora kinase inhibitors: novel small molecules with promising activity in acute myeloid and Philadelphia-positive leukemias.
  Leukemia, 24, 671-678.  
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.  
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
  20842194 O.V.Plotnikova, E.N.Pugacheva, R.L.Dunbrack, and E.A.Golemis (2010).
Rapid calcium-dependent activation of Aurora-A kinase.
  Nat Commun, 1, doi:10.1038/ncomms1061.  
19152640 H.Y.Wang, L.L.Li, Z.X.Cao, S.D.Luo, Y.Q.Wei, and S.Y.Yang (2009).
A Specific Pharmacophore Model of Aurora B Kinase Inhibitors and Virtual Screening Studies Based on it.
  Chem Biol Drug Des, 73, 115-126.  
19320832 N.Jetton, K.G.Rothberg, J.G.Hubbard, J.Wise, Y.Li, H.L.Ball, and L.Ruben (2009).
The cell cycle as a therapeutic target against Trypanosoma brucei: Hesperadin inhibits Aurora kinase-1 and blocks mitotic progression in bloodstream forms.
  Mol Microbiol, 72, 442-458.  
19825950 R.B.Cohen, S.F.Jones, C.Aggarwal, M.von Mehren, J.Cheng, D.R.Spigel, F.A.Greco, M.Mariani, M.Rocchetti, R.Ceruti, S.Comis, B.Laffranchi, J.Moll, and H.A.Burris (2009).
A phase I dose-escalation study of danusertib (PHA-739358) administered as a 24-hour infusion with and without granulocyte colony-stimulating factor in a 14-day cycle in patients with advanced solid tumors.
  Clin Cancer Res, 15, 6694-6701.  
19568282 S.Lapenna, and A.Giordano (2009).
Cell cycle kinases as therapeutic targets for cancer.
  Nat Rev Drug Discov, 8, 547-566.  
19823168 T.Ikezoe, T.Takeuchi, J.Yang, Y.Adachi, C.Nishioka, M.Furihata, H.P.Koeffler, and A.Yokoyama (2009).
Analysis of Aurora B kinase in non-Hodgkin lymphoma.
  Lab Invest, 89, 1364-1373.  
18268096 A.Gontarewicz, S.Balabanov, G.Keller, R.Colombo, A.Graziano, E.Pesenti, D.Benten, C.Bokemeyer, W.Fiedler, J.Moll, and T.H.Brümmendorf (2008).
Simultaneous targeting of Aurora kinases and Bcr-Abl kinase by the small molecule inhibitor PHA-739358 is effective against imatinib-resistant BCR-ABL mutations including T315I.
  Blood, 111, 4355-4364.  
18076371 P.Carpinelli, and J.Moll (2008).
Aurora kinase inhibitors: identification and preclinical validation of their biomarkers.
  Expert Opin Ther Targets, 12, 69-80.  
18759691 R.Tanaka, and S.Kimura (2008).
Abl tyrosine kinase inhibitors for overriding Bcr-Abl/T315I: from the second to third generation.
  Expert Rev Anticancer Ther, 8, 1387-1398.  
18518762 S.Padmanabhan, S.Ravella, T.Curiel, and F.Giles (2008).
Current status of therapy for chronic myeloid leukemia: a review of drug development.
  Future Oncol, 4, 359-377.  
18410307 X.Q.Deng, H.Y.Wang, Y.L.Zhao, M.L.Xiang, P.D.Jiang, Z.X.Cao, Y.Z.Zheng, S.D.Luo, L.T.Yu, Y.Q.Wei, and S.Y.Yang (2008).
Pharmacophore modelling and virtual screening for identification of new Aurora-A kinase inhibitors.
  Chem Biol Drug Des, 71, 533-539.  
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.  
17457302 E.Weisberg, P.W.Manley, S.W.Cowan-Jacob, A.Hochhaus, and J.D.Griffin (2007).
Second generation inhibitors of BCR-ABL for the treatment of imatinib-resistant chronic myeloid leukaemia.
  Nat Rev Cancer, 7, 345-356.  
17450625 M.G.Brasca, C.Albanese, R.Amici, D.Ballinari, L.Corti, V.Croci, D.Fancelli, F.Fiorentini, M.Nesi, P.Orsini, F.Orzi, W.Pastori, E.Perrone, E.Pesenti, P.Pevarello, F.Riccardi-Sirtori, F.Roletto, P.Roussel, M.Varasi, A.Vulpetti, and C.Mercurio (2007).
6-Substituted Pyrrolo[3,4-c]pyrazoles: An Improved Class of CDK2 Inhibitors.
  ChemMedChem, 2, 841-852.  
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 code is shown on the right.

 

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