4F1S

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

Summary for 4F1S

• Entry DOI: 10.2210/pdb4f1s/pdb
• Related: 4DK5
• Descriptor: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform, SULFATE ION, N-(5-{[3-(4-amino-6-methyl-1,3,5-triazin-2-yl)-5-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl]amino}-2-chloropyridin-3-yl)methanesulfonamide, ... (4 entities in total)
• Functional Keywords: phosphotransferase, lipid kinase, p85, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P48736
• Total number of polymer chains: 1
• Total formula weight: 110891.40

Authors

Whittington, D.A.,Tang, J.,Yakowec, P. (deposition date: 2012-05-07, release date: 2012-08-08, Last modification date: 2024-02-28)

Primary citation

Wurz, R.P.,Liu, L.,Yang, K.,Nishimura, N.,Bo, Y.,Pettus, L.H.,Caenepeel, S.,Freeman, D.J.,McCarter, J.D.,Mullady, E.L.,Miguel, T.S.,Wang, L.,Zhang, N.,Andrews, K.L.,Whittington, D.A.,Jiang, J.,Subramanian, R.,Hughes, P.E.,Norman, M.H.
Synthesis and structure-activity relationships of dual PI3K/mTOR inhibitors based on a 4-amino-6-methyl-1,3,5-triazine sulfonamide scaffold.
Bioorg.Med.Chem.Lett., 22:5714-5720, 2012

PubMed 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)=193 nM (91 ng/mL).

PubMed: 22832322
DOI: 10.1016/j.bmcl.2012.06.078

Experimental method

X-RAY DIFFRACTION (3 Å)