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PDBsum entry 3rwp

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protein ligands links
Transferase/transferase inhibitor PDB id
3rwp
Jmol PyMol
Contents
Protein chain
278 a.a.
Ligands
GOL ×4
SO4 ×6
ABQ
Waters ×205
PDB id:
3rwp
Name: Transferase/transferase inhibitor
Title: Discovery of a novel, potent and selective inhibitor of 3- phosphoinositide dependent kinase (pdk1)
Structure: 3-phosphoinositide-dependent protein kinase 1. Chain: a. Fragment: kinase domain, residues 51-359. Synonym: hpdk1. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: pdpk1, pdk1. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108
Resolution:
1.92Å     R-factor:   0.174     R-free:   0.213
Authors: S.E.Greasley,M.Hickey,R.-A.Ferre,M.Krauss,C.Cronin
Key ref: S.T.Murphy et al. (2011). Discovery of novel, potent, and selective inhibitors of 3-phosphoinositide-dependent kinase (PDK1). J Med Chem, 54, 8490-8500. PubMed id: 22040023 DOI: 10.1021/jm201019k
Date:
09-May-11     Release date:   16-Nov-11    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
O15530  (PDPK1_HUMAN) -  3-phosphoinositide-dependent protein kinase 1
Seq:
Struc:
 
Seq:
Struc:
556 a.a.
278 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: 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!
  Biological process     protein phosphorylation   1 term 
  Biochemical function     protein kinase activity     2 terms  

 

 
    reference    
 
 
DOI no: 10.1021/jm201019k J Med Chem 54:8490-8500 (2011)
PubMed id: 22040023  
 
 
Discovery of novel, potent, and selective inhibitors of 3-phosphoinositide-dependent kinase (PDK1).
S.T.Murphy, G.Alton, S.Bailey, S.M.Baxi, B.J.Burke, T.A.Chappie, J.Ermolieff, R.Ferre, S.Greasley, M.Hickey, J.Humphrey, N.Kablaoui, J.Kath, S.Kazmirski, M.Kraus, S.Kupchinsky, J.Li, L.Lingardo, M.A.Marx, D.Richter, S.P.Tanis, K.Tran, W.Vernier, Z.Xie, M.J.Yin, X.H.Yu.
 
  ABSTRACT  
 
Analogues substituted with various amines at the 6-position of the pyrazine ring on (4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyrazin-2-ylmethanone were discovered as potent and selective inhibitors of PDK1 with potential as anticancer agents. An early lead with 2-pyridine-3-ylethylamine as the pyrazine substituent showed moderate potency and selectivity. Structure-based drug design led to improved potency and selectivity against PI3Kα through a combination of cyclizing the ethylene spacer into a saturated, five-membered ring and substituting on the 4-position of the aryl ring with a fluorine. ADME properties were improved by lowering the lipophilicity with heteroatom replacements in the saturated, five-membered ring. The optimized analogues have a PDK1 Ki of 1 nM and >100-fold selectivity against PI3K/AKT-pathway kinases. The cellular potency of these analogues was assessed by the inhibition of AKT phosphorylation (T308) and by their antiproliferation activity against a number of tumor cell lines.
 

 

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