4f1s | pdb_00004f1s

Crystal structure of human PI3K-gamma in complex with a pyridyl-triazine-sulfonamide inhibitor

spinqualitylabelsall models 4f1s, resolution 3.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4f1s is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: F1S, SO4 Related: 4dk5 Gene: PIK3CG (Homo sapiens) Resources: FirstGlance, OCA, RCSB, PDBsum Publication Abstract from PubMed 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). Synthesis and structure-activity relationships of dual PI3K/mTOR inhibitors based on a 4-amino-6-methyl-1,3,5-triazine sulfonamide scaffold.,Wurz RP, Liu L, Yang K, Nishimura N, Bo Y, Pettus LH, Caenepeel S, Freeman DJ, McCarter JD, Mullady EL, Miguel TS, Wang L, Zhang N, Andrews KL, Whittington DA, Jiang J, Subramanian R, Hughes PE, Norman MH Bioorg Med Chem Lett. 2012 Jul 3. PMID:22832322 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Phosphoinositide 3-Kinases

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