3QAR

Crystal structure of PI3K-gamma in complex with triazine-benzimidazole 32

Summary for 3QAR

• Entry DOI: 10.2210/pdb3qar/pdb
• Related: 3QAQ
• Descriptor: Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma isoform, SULFATE ION, 1-(4-amino-6-methyl-1,3,5-triazin-2-yl)-N-(1H-pyrazol-3-yl)-1H-benzimidazol-2-amine, ... (4 entities in total)
• Functional Keywords: inhibitor, p110, kinase, transferase, atp-binding, p84, p101, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 110419.56

Authors

Whittington, D.A.,Tang, J.,Yakowec, P. (deposition date: 2011-01-11, release date: 2011-03-30, Last modification date: 2023-09-13)

Primary citation

Peterson, E.A.,Andrews, P.S.,Be, X.,Boezio, A.A.,Bush, T.L.,Cheng, A.C.,Coats, J.R.,Colletti, A.E.,Copeland, K.W.,Dupont, M.,Graceffa, R.,Grubinska, B.,Harmange, J.C.,Kim, J.L.,Mullady, E.L.,Olivieri, P.,Schenkel, L.B.,Stanton, M.K.,Teffera, Y.,Whittington, D.A.,Cai, T.,La, D.S.
Discovery of triazine-benzimidazoles as selective inhibitors of mTOR.
Bioorg.Med.Chem.Lett., 21:2064-2070, 2011

PubMed Abstract: mTOR is part of the PI3K/AKT pathway and is a central regulator of cell growth and survival. Since many cancers display mutations linked to the mTOR signaling pathway, mTOR has emerged as an important target for oncology therapy. Herein, we report the discovery of triazine benzimidazole inhibitors that inhibit mTOR kinase activity with up to 200-fold selectivity over the structurally homologous kinase PI3Kα. When tested in a panel of cancer cell lines displaying various mutations, a selective inhibitor from this series inhibited cellular proliferation with a mean IC(50) of 0.41 μM. Lead compound 42 demonstrated up to 83% inhibition of mTOR substrate phosphorylation in a murine pharmacodynamic model.

PubMed: 21376583
DOI: 10.1016/j.bmcl.2011.02.007

Experimental method

X-RAY DIFFRACTION (2.65 Å)