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PDBsum entry 3l13

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protein ligands links
Transferase PDB id
3l13
Jmol
Contents
Protein chain
841 a.a. *
Ligands
JZW
* Residue conservation analysis
PDB id:
3l13
Name: Transferase
Title: Crystal structures of pan-pi3-kinase and dual pan-pi3-kinase inhibitors
Structure: Phosphatidylinositol-4,5-bisphosphate 3-kinase ca subunit gamma isoform. Chain: a. Fragment: unp residues 144-1102. Synonym: pi3-kinase p110 subunit gamma, ptdins-3-kinase sub pi3kgamma, pi3k, p120-pi3k. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: pik3cg. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.
Resolution:
3.00Å     R-factor:   0.233     R-free:   0.275
Authors: J.M.Murray,C.Wiesmann
Key ref: D.P.Sutherlin et al. (2010). Discovery of (thienopyrimidin-2-yl)aminopyrimidines as potent, selective, and orally available pan-PI3-kinase and dual pan-PI3-kinase/mTOR inhibitors for the treatment of cancer. J Med Chem, 53, 1086-1097. PubMed id: 20050669 DOI: 10.1021/jm901284w
Date:
10-Dec-09     Release date:   16-Feb-10    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P48736  (PK3CG_HUMAN) -  Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
1102 a.a.
841 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class 2: E.C.2.7.1.153  - Phosphatidylinositol-4,5-bisphosphate 3-kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

      Pathway:
1-Phosphatidyl-myo-inositol Metabolism
      Reaction: ATP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate = ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
ATP
+ 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
= ADP
+ 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
   Enzyme class 3: 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
Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     phosphatidylinositol-mediated signaling   2 terms 
  Biochemical function     transferase activity, transferring phosphorus-containing groups     2 terms  

 

 
    reference    
 
 
DOI no: 10.1021/jm901284w J Med Chem 53:1086-1097 (2010)
PubMed id: 20050669  
 
 
Discovery of (thienopyrimidin-2-yl)aminopyrimidines as potent, selective, and orally available pan-PI3-kinase and dual pan-PI3-kinase/mTOR inhibitors for the treatment of cancer.
D.P.Sutherlin, D.Sampath, M.Berry, G.Castanedo, Z.Chang, I.Chuckowree, J.Dotson, A.Folkes, L.Friedman, R.Goldsmith, T.Heffron, L.Lee, J.Lesnick, C.Lewis, S.Mathieu, J.Nonomiya, A.Olivero, J.Pang, W.W.Prior, L.Salphati, S.Sideris, Q.Tian, V.Tsui, N.C.Wan, S.Wang, C.Wiesmann, S.Wong, B.Y.Zhu.
 
  ABSTRACT  
 
The PI3K/AKT/mTOR pathway has been shown to play an important role in cancer. Starting with compounds 1 and 2 (GDC-0941) as templates, (thienopyrimidin-2-yl)aminopyrimidines were discovered as potent inhibitors of PI3K or both PI3K and mTOR. Structural information derived from PI3K gamma-ligand cocrystal structures of 1 and 2 were used to design inhibitors that maintained potency for PI3K yet improved metabolic stability and oral bioavailability relative to 1. The addition of a single methyl group to the optimized 5 resulted in 21, which had significantly reduced potency for mTOR. The lead compounds 5 (GNE-493) and 21 (GNE-490) have good pharmacokinetic (PK) parameters, are highly selective, demonstrate knock down of pathway markers in vivo, and are efficacious in xenograft models where the PI3K pathway is deregulated. Both compounds were compared in a PI3K alpha mutated MCF7.1 xenograft model and were found to have equivalent efficacy when normalized for exposure.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21048785 J.Werzowa, S.Koehrer, S.Strommer, D.Cejka, T.Fuereder, E.Zebedin, and V.Wacheck (2011).
Vertical inhibition of the mTORC1/mTORC2/PI3K pathway shows synergistic effects against melanoma in vitro and in vivo.
  J Invest Dermatol, 131, 495-503.  
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