3LJ3

PI3-kinase-gamma with a pyrrolopyridine-benzofuran inhibitor

Summary for 3LJ3

• Entry DOI: 10.2210/pdb3lj3/pdb
• Descriptor: Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma isoform, SULFATE ION, (2Z)-4,6-dihydroxy-2-{[1-methyl-4-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]methylidene}-1-benzofuran-3(2H)-one, ... (4 entities in total)
• Functional Keywords: atp-binding, kinase, nucleotide-binding, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P48736
• Total number of polymer chains: 1
• Total formula weight: 111354.72

Authors

Bard, J.,Svenson, K. (deposition date: 2010-01-25, release date: 2010-04-14, Last modification date: 2023-09-06)

Primary citation

Tsou, H.R.,MacEwan, G.,Birnberg, G.,Grosu, G.,Bursavich, M.G.,Bard, J.,Brooijmans, N.,Toral-Barza, L.,Hollander, I.,Mansour, T.S.,Ayral-Kaloustian, S.,Yu, K.
Discovery and optimization of 2-(4-substituted-pyrrolo[2,3-b]pyridin-3-yl)methylene-4-hydroxybenzofuran-3(2H)-ones as potent and selective ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR).
Bioorg.Med.Chem.Lett., 20:2321-2325, 2010

PubMed Abstract: We discovered 2-(4-substituted-pyrrolo[2,3-b]pyridin-3-yl)methylene-4-hydroxybenzofuran-3(2H)-ones as potent and selective ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR). Since phenolic OH groups pose metabolic liability, one of the two hydroxyl groups was selectively removed. The SAR data showed the structural features necessary for subnanomolar inhibitory activity against mTOR kinase as well as selectivity over PI3Kalpha. An X-ray co-crystal structure of one inhibitor with the mTOR-related PI3Kgamma revealed the key hydrogen bonding interactions.

PubMed: 20188552
DOI: 10.1016/j.bmcl.2010.01.135

Experimental method

X-RAY DIFFRACTION (2.43 Å)