Interactions of LY 333531 and Other
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چکیده
family members, which is thought to contribute to the enhanced proliferation and survival of these cells. Be-Dundee DD1 5EH Scotland cause of this, there is considerable interest in developing inhibitors of PDK1 and other members of the AGC kinase 4 Drug Discovery Program Department of Neurology family. Much attention has been devoted to a group of bisin-dolyl maleimide compounds that are based on the scaffold of the nonspecific kinase inhibitor staurosporine (reviewed in Goekjian and Jirousek, 1999). These BIM compounds were originally reported to function as PKC Summary selective inhibitors (Davis et al., 1992b), although subsequent work indicated that these were less specific than LY333531, BIM-1, BIM-2, BIM-3, and BIM-8 are bisin-dolyl maleimide-based, nanomolar protein kinase C originally thought (Davies et al., 2000). A structurally related inhibitor termed LY333531 was also developed, inhibitors. LY333531, a PKC-specific inhibitor, is in clinical trials against diabetes and cardiac ventricular which appeared to be more specific than other BIM compounds and inhibited the PKC isoform with two hypertrophy complications. Specificity analysis with a panel of 29 protein kinases reveals that these bisindo-orders of magnitude higher potency than other PKC isoforms (Goekjian and Jirousek, 1999; Jirousek et al., lyl maleimide inhibitors also inhibit PDK1, a key kinase from the insulin signaling pathway, albeit in the lower 1996). Currently, LY333531 is in phase III clinical trials as a therapeutic agent for prevention of diabetes compli-M range. To understand the molecular basis of inhibition , the PDK1 kinase domain was cocrystallized with cations such as diabetic retinopathy (Nakamura et al., 1999), and also against left ventricular hypertrophy in these bisindolyl maleimide inhibitors. The inhibitor complexes represent the first structural description of this heart failure, the latter probably due to effects on calcium sensitivity (Vlahos et al., 2003). class of compounds, revealing their unusual nonplanar conformation within the ATP binding site and also ex-The BIM and LY333531 inhibitors chemically differ from staurosporine by the lack of a second covalent plaining the higher inhibitory potential of LY33331 compared to the BIM compounds toward PDK1. A combina-bond between the indole rings and by a change in the head group from a lactam to a maleimide moiety tion of site-directed mutagenesis and essential dynamics analysis gives further insight into PDK1 and also PKC (Figures 1A–1F). These compounds are synthetically more accessible than staurosporine, and a large number inhibition by these compounds, and may aid inhibitor design. of these derivatives have been …
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