4F1S: Crystal Structure Of Human Pi3k-Gamma In Complex With A Pyridyl- Triazine-Sulfonamide Inhibitor

Citation:
Abstract
Phosphoinositide 3-kinase (PI3K) is an important target in oncology due to the deregulation of the PI3K/Akt signaling pathway in a wide variety of tumors. A series of 4-amino-6-methyl-1,3,5-triazine sulfonamides were synthesized and evaluated as inhibitors of PI3K. The synthesis, in vitro biological activities, pharmacokinetic and in vivo pharmacodynamic profiling of these compounds are described. The most promising compound from this investigation (compound 3j) was found to be a pan class I PI3K inhibitor with a moderate (>10-fold) selectivity over the mammalian target of rapamycin (mTOR) in the enzyme assay. In a U87 MG cellular assay measuring phosphorylation of Akt, compound 3j displayed low double digit nanomolar IC(50) and exhibited good oral bioavailability in rats (F(oral)=63%). Compound 3j also showed a dose dependent reduction in the phosphorylation of Akt in a U87 tumor pharmacodynamic model with a plasma EC(50)=193nM (91ng/mL).
PDB ID: 4F1SDownload
MMDB ID: 101886
PDB Deposition Date: 2012/5/7
Updated in MMDB: 2012/09
Experimental Method:
x-ray diffraction
Resolution: 3  Å
Source Organism:
Similar Structures:
Biological Unit for 4F1S: monomeric; determined by author and by software (PISA)
Molecular Components in 4F1S
Label Count Molecule
Protein (1 molecule)
1
Phosphatidylinositol 4,5-bisphosphate 3-kinase CA Subunit Gamma Isoform(Gene symbol: PIK3CG)
Molecule annotation
Chemicals (7 molecules)
1
6
2
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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