2002
DOI: 10.1074/jbc.m202651200
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Intracellular Targets of Paullones

Abstract: Numerous inhibitors of cyclin-dependent kinases and glycogen synthase kinase-3 (GSK-3) are being developed in view of their potential applications against cancers and neurodegenerative disorders. Among these, paullones constitute a family of potent and apparently selective cyclin-dependent kinase and GSK-3 inhibitors. However, their actual intracellular targets remain to be identified. To address this issue we have immobilized a paullone, gwennpaullone, on an agarose matrix. Extracts from various cell types an… Show more

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Cited by 136 publications
(89 citation statements)
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“…CDK1, 2 and 7 were found to bind purvalanol beads in seven different mammalian cell lines (Figure 5b; Knockaert et al, 2000;Schang et al, 2001). CDK5 was recovered on the purvalanol matrix from porcine and human brain extracts (Knockaert et al, 2000; data not shown) and sea urchin eggs (Knockaert et al, 2002b). This is not surprising, as purvalanols are potent CDK inhibitors that are highly selective for CDK1, 2, 5 and 7 over other members of the CDK family (Gray et al, 1998;Chang et al, 1999;Rosania et al, 1999).…”
Section: Purvalanol Inhibits Cdks In Vivomentioning
confidence: 87%
See 1 more Smart Citation
“…CDK1, 2 and 7 were found to bind purvalanol beads in seven different mammalian cell lines (Figure 5b; Knockaert et al, 2000;Schang et al, 2001). CDK5 was recovered on the purvalanol matrix from porcine and human brain extracts (Knockaert et al, 2000; data not shown) and sea urchin eggs (Knockaert et al, 2002b). This is not surprising, as purvalanols are potent CDK inhibitors that are highly selective for CDK1, 2, 5 and 7 over other members of the CDK family (Gray et al, 1998;Chang et al, 1999;Rosania et al, 1999).…”
Section: Purvalanol Inhibits Cdks In Vivomentioning
confidence: 87%
“…Using the same affinity chromatography approach, several unexpected targets of CDK inhibitors have been identified: glycogen phosphorylase for flavopiridol (Schnier et al, 1999;Oikonomakos et al, 2000;Kaiser et al, 2001), mitochondrial malate dehydrogenase and glycogen synthase kinase-3 for paullones (Knockaert et al, 2002b), casein kinase 1 in Plasmodium falciparum for purvalanol (Knockaert et al, 2000). In all cases, the unexpected target enzymes were inhibited by the free compound.…”
Section: Purine Inhibitors Of Cdks the Selectivity Problemmentioning
confidence: 99%
“…This suggests that inhibitors of Cdk5 activity may be effective candidates for therapeutic development (25,70,71). Although several potent chemical inhibitors of Cdk5 have been identified and studied (26,72,73), most compete with ATP at the catalytic binding site. Accordingly, these compounds are relatively nonspecific because other cyclin-dependent kinases (as well as other kinases) are equally dependent on ATP binding.…”
Section: Discussionmentioning
confidence: 99%
“…These data indicate that GSK-3␤ has the capacity to directly phosphorylate MLK3 in vitro. To assess whether this reaction occurred in vivo, we employed metabolic 32 P labeling experiments in HEK-293 cells. These experiments showed that active GSK-3␤ was capable of phosphorylating full-length, kinase-inactive MLK3 under in vivo conditions, whereas phosphorylation of MLK3 by inactive GSK-3␤ was insignificant (Fig.…”
Section: Ngf Withdrawal Induces Gsk-3␤ Mlk3 and Jnk Protein Kinase mentioning
confidence: 99%