spacer
spacer

PDBsum entry 2vtj

Go to PDB code: 
protein ligands links
Transferase PDB id
2vtj
Jmol
Contents
Protein chain
276 a.a. *
Ligands
GOL
LZ4
Waters ×160
* Residue conservation analysis
PDB id:
2vtj
Name: Transferase
Title: Identification of n-(4-piperidinyl)-4-(2,6- dichlorobenzoylamino)-1h-pyrazole-3-carboxamide (at7519), a novel cyclin dependent kinase inhibitor using fragment- based x-ray crystallography and structure based drug design
Structure: Cell division protein kinase 2. Chain: a. Synonym: p33 protein kinase, cyclin dependent kinase 2. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9.
Resolution:
2.20Å     R-factor:   0.189     R-free:   0.262
Authors: P.G.Wyatt,A.J.Woodhead,J.A.Boulstridge,V.Berdini,M.G.Carr,D. D.Danillon,D.J.Davis,L.A.Devine,T.R.Early,R.E.Feltell,E.J.L R.L.Mcmenamin,E.F.Navarro,M.A.O'Brien,M.O'Reilly,M.Reule,G. L.C.A.Seavers,D.Smith,M.S.Squires,G.Trewartha,M.T.Walker, A.J.Woolford
Key ref: P.G.Wyatt et al. (2008). Identification of N-(4-piperidinyl)-4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxamide (AT7519), a novel cyclin dependent kinase inhibitor using fragment-based X-ray crystallography and structure based drug design. J Med Chem, 51, 4986-4999. PubMed id: 18656911 DOI: 10.1021/jm800382h
Date:
15-May-08     Release date:   05-Aug-08    
PROCHECK
Go to PROCHECK summary
 Headers
 References

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

 Enzyme reactions 
   Enzyme class: E.C.2.7.11.22  - Cyclin-dependent kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a protein = ADP + a phosphoprotein
ATP
+ protein
= ADP
+ 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   27 terms 
  Biochemical function     nucleotide binding     12 terms  

 

 
    reference    
 
 
DOI no: 10.1021/jm800382h J Med Chem 51:4986-4999 (2008)
PubMed id: 18656911  
 
 
Identification of N-(4-piperidinyl)-4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxamide (AT7519), a novel cyclin dependent kinase inhibitor using fragment-based X-ray crystallography and structure based drug design.
P.G.Wyatt, A.J.Woodhead, V.Berdini, J.A.Boulstridge, M.G.Carr, D.M.Cross, D.J.Davis, L.A.Devine, T.R.Early, R.E.Feltell, E.J.Lewis, R.L.McMenamin, E.F.Navarro, M.A.O'Brien, M.O'Reilly, M.Reule, G.Saxty, L.C.Seavers, D.M.Smith, M.S.Squires, G.Trewartha, M.T.Walker, A.J.Woolford.
 
  ABSTRACT  
 
The application of fragment-based screening techniques to cyclin dependent kinase 2 (CDK2) identified multiple (>30) efficient, synthetically tractable small molecule hits for further optimization. Structure-based design approaches led to the identification of multiple lead series, which retained the key interactions of the initial binding fragments and additionally explored other areas of the ATP binding site. The majority of this paper details the structure-guided optimization of indazole (6) using information gained from multiple ligand-CDK2 cocrystal structures. Identification of key binding features for this class of compounds resulted in a series of molecules with low nM affinity for CDK2. Optimisation of cellular activity and characterization of pharmacokinetic properties led to the identification of 33 (AT7519), which is currently being evaluated in clinical trials for the treatment of human cancers.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21223249 D.W.McMillin, J.Delmore, J.Negri, L.Buon, H.M.Jacobs, J.Laubach, J.Jakubikova, M.Ooi, P.Hayden, R.Schlossman, N.C.Munshi, C.Lengauer, P.G.Richardson, K.C.Anderson, and C.S.Mitsiades (2011).
Molecular and cellular effects of multi-targeted cyclin-dependent kinase inhibition in myeloma: biological and clinical implications.
  Br J Haematol, 152, 420-432.  
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.  
21536436 P.Vella, W.M.Hussein, E.W.Leung, D.Clayton, D.L.Ollis, N.Mitić, G.Schenk, and R.P.McGeary (2011).
The identification of new metallo-β-lactamase inhibitor leads from fragment-based screening.
  Bioorg Med Chem Lett, 21, 3282-3285.  
20471246 C.W.Murray, and T.L.Blundell (2010).
Structural biology in fragment-based drug design.
  Curr Opin Struct Biol, 20, 497-507.  
20448906 C.Wong, R.J.Griffin, I.R.Hardcastle, J.S.Northen, L.Z.Wang, and B.T.Golding (2010).
Synthesis of sulfonamide-based kinase inhibitors from sulfonates by exploiting the abrogated SN2 reactivity of 2,2,2-trifluoroethoxysulfonates.
  Org Biomol Chem, 8, 2457-2464.  
20190516 D.Tanaka (2010).
[Fragment-based drug discovery: concept and aim].
  Yakugaku Zasshi, 130, 315-323.  
19944161 D.Z.Liu, B.P.Ander, and F.R.Sharp (2010).
Cell cycle inhibition without disruption of neurogenesis is a strategy for treatment of central nervous system diseases.
  Neurobiol Dis, 37, 549-557.  
20101221 L.Santo, S.Vallet, T.Hideshima, D.Cirstea, H.Ikeda, S.Pozzi, K.Patel, Y.Okawa, G.Gorgun, G.Perrone, E.Calabrese, M.Yule, M.Squires, M.Ladetto, M.Boccadoro, P.G.Richardson, N.C.Munshi, K.C.Anderson, and N.Raje (2010).
AT7519, A novel small molecule multi-cyclin-dependent kinase inhibitor, induces apoptosis in multiple myeloma via GSK-3beta activation and RNA polymerase II inhibition.
  Oncogene, 29, 2325-2336.  
20642456 N.Drinkwater, H.Vu, K.M.Lovell, K.R.Criscione, B.M.Collins, T.E.Prisinzano, S.A.Poulsen, M.J.McLeish, G.L.Grunewald, and J.L.Martin (2010).
Fragment-based screening by X-ray crystallography, MS and isothermal titration calorimetry to identify PNMT (phenylethanolamine N-methyltransferase) inhibitors.
  Biochem J, 431, 51-61.
PDB codes: 3kpj 3kpu 3kpv 3kpw 3kpy 3kqm 3kqo 3kqp 3kqq 3kqs 3kqt 3kqv 3kqw 3kqy 3kr0 3kr1 3kr2
19416920 D.G.Teotico, K.Babaoglu, G.J.Rocklin, R.S.Ferreira, A.M.Giannetti, and B.K.Shoichet (2009).
Docking for fragment inhibitors of AmpC beta-lactamase.
  Proc Natl Acad Sci U S A, 106, 7455-7460.
PDB codes: 3gqz 3gr2 3grj 3gsg 3gtc 3gv9 3gvb
19427404 G.Chessari, and A.J.Woodhead (2009).
From fragment to clinical candidate--a historical perspective.
  Drug Discov Today, 14, 668-675.  
19443265 G.E.de Kloe, D.Bailey, R.Leurs, and I.J.de Esch (2009).
Transforming fragments into candidates: small becomes big in medicinal chemistry.
  Drug Discov Today, 14, 630-646.  
19104514 J.Zhang, P.L.Yang, and N.S.Gray (2009).
Targeting cancer with small molecule kinase inhibitors.
  Nat Rev Cancer, 9, 28-39.  
19296866 L.N.Johnson (2009).
Protein kinase inhibitors: contributions from structure to clinical compounds.
  Q Rev Biophys, 42, 1.  
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.