The identification of 8,9-dimethoxy-5-(2-aminoalkoxy-pyridin-3-yl)-benzo[c][2,7]naphthyridin-4-ylamines as potent inhibitors of 3-phosphoinositide-dependent kinase-1 (PDK-1).

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Nittoli T, Dushin RG, Ingalls C, Cheung K, Floyd MB, Fraser H, Olland A, Hu Y, Grosu G, Han X, Arndt K, Guo B, Wissner A

The identification of 8,9-dimethoxy-5-(2-aminoalkoxy-pyridin-3-yl)-benzo[c][2,7]naphthyridin-4-ylamines as potent inhibitors of 3-phosphoinositide-dependent kinase-1 (PDK-1).

Eur J Med Chem. 2010 Apr;45(4):1379-86. doi: 10.1016/j.ejmech.2009.12.036. Epub 2009 Dec 28.

PubMed ID

20074837 [ View in PubMed

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Abstract

A series of 8,9-dimethoxy-5-(2-aminoalkoxy-pyridin-3-yl)-benzo[c][2,7]naphthyridin-4-ylamine- based inhibitors of 3-phosphoinositide-dependent kinase-1 (PDK-1) has been identified. Several examples appear to be potent and relatively selective inhibitors of PDK-1 over the related AGC kinases PKA, PKB/AKT, and p70S6K. The introduction of a stereochemical center beside the amino substituent on the aminoalkoxy-side chain had little effect upon the inhibitory activity against these enzymes, and X-ray crystallographic analyses of a representative pair of enantiomeric inhibitors bound to the active site of PDK-1 revealed comparable binding modes for each enantiomer.

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Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
10,11-dimethoxy-4-methyldibenzo[c,f]-2,7-naphthyridine-3,6-diamine	3-phosphoinositide-dependent protein kinase 1	IC 50 (nM)	60	N/A	N/A	Details