Interactions of LY333531 and other bisindolyl maleimide inhibitors with PDK1.

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Komander D, Kular GS, Schuttelkopf AW, Deak M, Prakash KR, Bain J, Elliott M, Garrido-Franco M, Kozikowski AP, Alessi DR, van Aalten DM

Interactions of LY333531 and other bisindolyl maleimide inhibitors with PDK1.

Structure. 2004 Feb;12(2):215-26.

PubMed ID
14962382 [ View in PubMed
]
Abstract

LY333531, BIM-1, BIM-2, BIM-3, and BIM-8 are bisindolyl maleimide-based, nanomolar protein kinase C inhibitors. LY333531, a PKCbeta-specific inhibitor, is in clinical trials against diabetes and cardiac ventricular hypertrophy complications. Specificity analysis with a panel of 29 protein kinases reveals that these bisindolyl maleimide inhibitors also inhibit PDK1, a key kinase from the insulin signaling pathway, albeit in the lower microM range. To understand the molecular basis of inhibition, the PDK1 kinase domain was cocrystallized with these bisindolyl maleimide inhibitors. The inhibitor complexes represent the first structural description of this class of compounds, revealing their unusual nonplanar conformation within the ATP binding site and also explaining the higher inhibitory potential of LY33331 compared to the BIM compounds toward PDK1. A combination of site-directed mutagenesis and essential dynamics analysis gives further insight into PDK1 and also PKC inhibition by these compounds, and may aid inhibitor design.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
3-[1-(3-AMINOPROPYL)-1H-INDOL-3-YL]-4-(1H-INDOL-3-YL)-1H-PYRROLE-2,5-DIONE3-phosphoinositide-dependent protein kinase 1IC 50 (nM)40007.530Details
7-Hydroxystaurosporine3-phosphoinositide-dependent protein kinase 1IC 50 (nM)67.530Details
Bisindolylmaleimide I3-phosphoinositide-dependent protein kinase 1IC 50 (nM)90007.530Details
Bisindolylmaleimide VIII3-phosphoinositide-dependent protein kinase 1IC 50 (nM)10007.530Details