Protein kinase inhibition by staurosporine revealed in details of the molecular interaction with CDK2

Lawrie, Alison M.; Noble, M.E.M.; Tunnah, Paul; Brown, Nicholas R.; Johnson, L.N.; Endicott, J.A.

doi:10.1038/nsb1097-796

Cited by 260 publications

(201 citation statements)

References 36 publications

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“…In apo-Met, one water molecule is present at the position of the lactam nitrogen and another water molecule is close to the position of the lactam oxygen. Water molecules in the corresponding positions have also been reported for apo-CDK2 (17). Three additional hydrogen bonds, unique to this complex, are formed with atoms from the K-252a furanose moiety.…”

Section: Resultsmentioning

confidence: 89%

“…Structures of staurosporine in complex with the Ser͞Thr kinase domains of CDK2 and protein kinase A (PKA), as well as the tyrosine kinase domains of CSK and Lck, have been reported (16)(17)(18)(19). They revealed a common binding mode in the adenosine cleft, induced conformational changes of the enzyme to accommodate the large compound through a complementary apolar interaction surface, and specific hydrogen-bonding interactions (for recent reviews on kinase structure and inhibition, see refs.…”

mentioning

confidence: 99%

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Crystal structure of the tyrosine kinase domain of the hepatocyte growth factor receptor c-Met and its complex with the microbial alkaloid K-252a

Schiering

Knapp²,

Marconi³

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

140

133

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Section: Resultsmentioning

confidence: 89%

mentioning

confidence: 99%

Crystal structure of the tyrosine kinase domain of the hepatocyte growth factor receptor c-Met and its complex with the microbial alkaloid K-252a

Schiering

Knapp²,

Marconi³

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

140

133

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show abstract

“…The structure of 7 was confirmed by X-ray crystallographic analysis. The ring expansion of the indigo 5-membered ring into a 6-membered ring is new chemistry, with the three additional carbons of the indolo[1, 2-h] [1,7]naphthyridine parent structure being sourced from the additional propargyl unit.…”

Section: Synthesis and Structural Elucidationmentioning

confidence: 99%

“…Such biologically active natural products (e.g. with anti-cancer or antimicrobial activity) include fascaplysin 4 ; homofascaplysin 5 ; iheyamines 6 ; staurosporine 7 and Figure 1. Some biologically active natural products with an embedded 2,2´-diindolic unit.…”

Section: Introductionmentioning

confidence: 99%

Rapid Cascade Synthesis of Poly-Heterocyclic Architectures from Indigo

et al. 2013

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The base-induced propargylation of the dye indigo results in the rapid and unprecedented one-pot synthesis of highly functionalized representatives of the pyrazino[1,2-a:4,3-a′]diindole, pyrido[1,2-a:3,4-b′]diindole and benzo [b]indolo [1,2-h]naphthyridine heterocyclic systems, with the last two reflecting the core skeleton of the anticancer/antiplasmodial marine natural products fascaplysin and homofascaplysins and a ring Bhomologue, respectively. The polycyclic compounds 6-8, whose structures were confirmed through singlecrystal X-ray crystallographic analysis, arise from sequential inter/intramolecular substitution-addition reactions, and in some cases, ring rearrangement reactions. Preliminary studies on controlling the reaction path selectivity, and the potential reaction mechanisms, are also described. Initial biological activity studies with these new heterocyclic derivatives indicated promising in vitro antiplasmodial activity as well as good anticancer activity. The chemistry described is new for the indigo moiety and cascade reactions from this readily available and cheap starting material should be more broadly applicable in the synthesis of additional new heterocyclic systems difficult to access by other means. Preliminary studies on controlling the reaction path selectivity, and the potential reaction mechanisms, are also described. Initial biological activity studies with these new heterocyclic derivatives indicated promising in vitro anti-plasmodial activity as well as good anti-cancer activity. The chemistry described is new for the indigo moiety and cascade reactions from this readily available and cheap starting material should be applicable more broadly in the synthesis of additional new heterocyclic systems difficult to access by other means.

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“…Because the bisindolylmaleimide scaffold is very similar to the indolocarbazole core structure of staurosporine, we decided to dock BisIII, BisVIII, and BisX into the published structure of CDK2 in complex with staurosporine (1AQ1) (Fig. 8, A-C) (19). As shown for BisX in Fig.…”

Section: Fig 6 Slk Is a Potent Target Of Bisiiimentioning

confidence: 99%

Proteome-wide Identification of Cellular Targets Affected by Bisindolylmaleimide-type Protein Kinase C Inhibitors

Brehmer

Godl

Zech

et al. 2004

Molecular & Cellular Proteomics

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Bisindolylmaleimide compounds such as GF109203X are potent inhibitors of protein kinase C (PKC) activity. Although bisindolylmaleimides are not entirely selective for PKC and are known to inhibit a few other protein kinases, these reagents have been extensively used to study the functional roles of PKC family enzymes in cellular signal transduction for more than a decade. Here, we establish a proteomics approach to gain further insights into the cellular effects of this compound class. Functional immobilization of suitable bisindolylmaleimide analogues in combination with the specific purification of cellular binding proteins by affinity chromatography led to the identification of several known and previously unknown enzyme targets. Subsequent in vitro binding and activity assays confirmed the protein kinases Ste20-related kinase and cyclin-dependent kinase 2 (CDK2) and the non-protein kinases adenosine kinase and quinone reductase type 2 as novel targets of bisindolylmaleimide inhibitors. As observed specifically for CDK2, minor chemical variation of the ligand by immobilizing the closely related bisindolylmaleimides III, VIII, and X dramatically affected target binding. These observed changes in affinity correlated with both the measured IC 50 values for in vitro CDK2 inhibition and results from molecular docking into the CDK2 crystal structure. Moreover, the conditions for affinity purification could be adapted in a way that immobilized bisindolylmaleimide III selectively interacted with either PKC␣ or ribosomal S6 protein kinase 1 only after activation of these kinases. Thus, we have established an efficient technique for the rapid identification of cellular bisindolylmaleimide targets and further demonstrate the comparative selectivity profiling of closely related kinase inhibitors within a cellular proteome. Molecular & Cellular Proteomics 3:490 -500, 2004.

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Protein kinase inhibition by staurosporine revealed in details of the molecular interaction with CDK2

Abstract: Staurosporine exhibits nanomolar IC50 values against a wide range of protein kinases. The structure of a CDK2 staurosporine complex explains the tight binding of this inhibitor, and suggests features to be exploited in the design of specific inhibitors of CDKs.

Cited by 260 publications

References 36 publications

Crystal structure of the tyrosine kinase domain of the hepatocyte growth factor receptor c-Met and its complex with the microbial alkaloid K-252a

Crystal structure of the tyrosine kinase domain of the hepatocyte growth factor receptor c-Met and its complex with the microbial alkaloid K-252a

Rapid Cascade Synthesis of Poly-Heterocyclic Architectures from Indigo

Proteome-wide Identification of Cellular Targets Affected by Bisindolylmaleimide-type Protein Kinase C Inhibitors

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