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PDBsum entry 3ml9

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protein ligands links
Transferase/transferase inhibitor PDB id
3ml9
Jmol
Contents
Protein chain
847 a.a. *
Ligands
ML9
Waters ×1
* Residue conservation analysis
PDB id:
3ml9
Name: Transferase/transferase inhibitor
Title: Discovery of the highly potent pi3k/mtor dual inhibitor pf-0 through structure based drug design
Structure: Phosphatidylinositol-4,5-bisphosphate 3-kinase ca subunit gamma isoform. Chain: a. Synonym: ptdins-3-kinase subunit gamma, pi3-kinase subunit pi3k-gamma, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma, ptdins-3-kinase subunit p110-gamma pi3k. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: pik3cg. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108
Resolution:
2.55Å     R-factor:   0.245     R-free:   0.298
Authors: D.R.Knighton
Key ref: H.Cheng et al. (2013). Discovery of the Highly Potent PI3K/mTOR Dual Inhibitor PF-04979064 through Structure-Based Drug Design. ACS Med Chem Lett, 4, 91-97. PubMed id: 24900568 DOI: 10.1021/ml300309h
Date:
16-Apr-10     Release date:   02-Jun-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.
847 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/ml300309h ACS Med Chem Lett 4:91-97 (2013)
PubMed id: 24900568  
 
 
Discovery of the Highly Potent PI3K/mTOR Dual Inhibitor PF-04979064 through Structure-Based Drug Design.
H.Cheng, C.Li, S.Bailey, S.M.Baxi, L.Goulet, L.Guo, J.Hoffman, Y.Jiang, T.O.Johnson, T.W.Johnson, D.R.Knighton, J.Li, K.K.Liu, Z.Liu, M.A.Marx, M.Walls, P.A.Wells, M.J.Yin, J.Zhu, M.Zientek.
 
  ABSTRACT  
 
PI3K, AKT, and mTOR are key kinases from PI3K signaling pathway being extensively pursued to treat a variety of cancers in oncology. To search for a structurally differentiated back-up candidate to PF-04691502, which is currently in phase I/II clinical trials for treating solid tumors, a lead optimization effort was carried out with a tricyclic imidazo[1,5]naphthyridine series. Integration of structure-based drug design and physical properties-based optimization yielded a potent and selective PI3K/mTOR dual kinase inhibitor PF-04979064. This manuscript discusses the lead optimization for the tricyclic series, which both improved the in vitro potency and addressed a number of ADMET issues including high metabolic clearance mediated by both P450 and aldehyde oxidase (AO), poor permeability, and poor solubility. An empirical scaling tool was developed to predict human clearance from in vitro human liver S9 assay data for tricyclic derivatives that were AO substrates.