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PDBsum entry 3tl5

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protein ligands links
Transferase/transferase inhibitor PDB id
3tl5
Jmol
Contents
Protein chain
845 a.a.
Ligands
980
Waters ×13
PDB id:
3tl5
Name: Transferase/transferase inhibitor
Title: Discovery of gdc-0980: a potent, selective, and orally avail i phosphatidylinositol 3-kinase (pi3k)/mammalian target of (mtor) kinase inhibitor for the treatment of cancer
Structure: Phosphatidylinositol-4,5-bisphosphate 3-kinase ca subunit gamma isoform. Chain: a. Fragment: unp residues 144-1102. Synonym: phosphoinositide 3-kinase p110-gamma-isoform, pi3- subunit gamma, pi3k-gamma, ptdins-3-kinase subunit gamma, phosphatidylinositol-4,5-bisphosphate 3-kinase 110 kda cata subunit gamma, ptdins-3-kinase subunit p110-gamma, p120-pi3 engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: pik3cg. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.
Resolution:
2.79Å     R-factor:   0.203     R-free:   0.267
Authors: J.M.Murray,C.Wiesmann
Key ref: D.P.Sutherlin et al. (2011). Discovery of a potent, selective, and orally available class I phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) kinase inhibitor (GDC-0980) for the treatment of cancer. J Med Chem, 54, 7579-7587. PubMed id: 21981714 DOI: 10.1021/jm2009327
Date:
29-Aug-11     Release date:   02-Nov-11    
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.
845 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/jm2009327 J Med Chem 54:7579-7587 (2011)
PubMed id: 21981714  
 
 
Discovery of a potent, selective, and orally available class I phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) kinase inhibitor (GDC-0980) for the treatment of cancer.
D.P.Sutherlin, L.Bao, M.Berry, G.Castanedo, I.Chuckowree, J.Dotson, A.Folks, L.Friedman, R.Goldsmith, J.Gunzner, T.Heffron, J.Lesnick, C.Lewis, S.Mathieu, J.Murray, J.Nonomiya, J.Pang, N.Pegg, W.W.Prior, L.Rouge, L.Salphati, D.Sampath, Q.Tian, V.Tsui, N.C.Wan, S.Wang, B.Wei, C.Wiesmann, P.Wu, B.Y.Zhu, A.Olivero.
 
  ABSTRACT  
 
The discovery of 2 (GDC-0980), a class I PI3K and mTOR kinase inhibitor for oncology indications, is described. mTOR inhibition was added to the class I PI3K inhibitor 1 (GDC-0941) scaffold primarily through the substitution of the indazole in 1 for a 2-aminopyrimidine. This substitution also increased the microsomal stability and the free fraction of compounds as evidenced through a pairwise comparison of molecules that were otherwise identical. Highlighted in detail are analogues of an advanced compound 4 that were designed to improve solubility, resulting in 2. This compound, is potent across PI3K class I isoforms with IC(50)s of 5, 27, 7, and 14 nM for PI3Kα, β, δ, and γ, respectively, inhibits mTOR with a K(i) of 17 nM yet is highly selective versus a large panel of kinases including others in the PIKK family. On the basis of the cell potency, low clearance in mouse, and high free fraction, 2 demonstrated significant efficacy in mouse xenografts when dosed as low as 1 mg/kg orally and is currently in phase I clinical trials for cancer.