3L08

Structure of Pi3K gamma with a potent inhibitor: GSK2126458

Summary for 3L08

• Entry DOI: 10.2210/pdb3l08/pdb
• Descriptor: Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma isoform, SULFATE ION, 2,4-difluoro-N-[2-methoxy-5-(4-pyridazin-4-ylquinolin-6-yl)pyridin-3-yl]benzenesulfonamide, ... (4 entities in total)
• Functional Keywords: pi3k gamma, lipid kinase, phosphoinositide, inhibitor, gsk2126458, signaling, kinase, atp-binding, nucleotide-binding, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm : P48736
• Total number of polymer chains: 1
• Total formula weight: 111424.72

Authors

Elkins, P.A.,Marrero, E.M. (deposition date: 2009-12-09, release date: 2010-06-23, Last modification date: 2024-04-03)

Primary citation

Knight, S.D.,Adams, N.D.,Burgess, J.L.,Chaudhari, A.M.,Darcy, M.G.,Donatelli, C.A.,Luengo, J.I.,Newlander, K.A.,Parrish, C.A.,Ridgers, L.H.,Sarpong, M.A.,Schmidt, S.J.,Van Aller, G.S.,Carson, J.D.,Diamond, M.A.,Elkins, P.A.,Gardiner, C.M.,Garver, E.,Gilbert, S.A.,Gontarek, R.R.,Jackson, J.R.,Kershner, K.L.,Luo, L.,Raha, K.,Sherk, C.S.,Sung, C.M.,Sutton, D.,Tummino, P.J.,Wegrzyn, R.J.,Auger, K.R.,Dhanak, D.
Discovery of GSK2126458, a Highly Potent Inhibitor of PI3K and the Mammalian Target of Rapamycin.
ACS Med Chem Lett, 1:39-43, 2010

PubMed Abstract: Phosphoinositide 3-kinase α (PI3Kα) is a critical regulator of cell growth and transformation, and its signaling pathway is the most commonly mutated pathway in human cancers. The mammalian target of rapamycin (mTOR), a class IV PI3K protein kinase, is also a central regulator of cell growth, and mTOR inhibitors are believed to augment the antiproliferative efficacy of PI3K/AKT pathway inhibition. 2,4-Difluoro-N-{2-(methyloxy)-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide (GSK2126458, 1) has been identified as a highly potent, orally bioavailable inhibitor of PI3Kα and mTOR with in vivo activity in both pharmacodynamic and tumor growth efficacy models. Compound 1 is currently being evaluated in human clinical trials for the treatment of cancer.

PubMed: 24900173
DOI: 10.1021/ml900028r

Experimental method

X-RAY DIFFRACTION (2.7 Å)