From the Insoluble Dye Indirubin towards Highly Active, Soluble CDK2‐Inhibitors

Jautelat, Rolf; Brumby, Thomas; Schäfer, Martina; Briem, Hans; Eisenbrand, Gerhard; Schwahn, S.; Krüger, Melanie; Lücking, Ulrich; Prien, Olaf; Siemeister, Gerhard

doi:10.1002/cbic.200400108

Cited by 81 publications

(83 citation statements)

References 24 publications

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“…In particular, numerous modifications have been carried out on positions 3 0 , 5 0 , 6 0 on one indole ring and 5 or 6 on the other indole ring (Hoessel et al, 1999;Leclerc et al, 2001;Meijer et al, 2003;Merz et al, 2004;Polychronopoulos et al, 2004;Jautelat et al, 2005). However, no modifications have ever been reported on position 7.…”

Section: Discussionmentioning

confidence: 99%

“…This approach first revealed that Aurora A-C, FMS-like tyrosine kinase 3 (FLT3), RET constitute new targets of IO, 5BIO and 6BIO. Vascular endothelial growth factor receptor (VEGF-R) had been previously described as a target for indirubins (Jautelat et al, 2005). The selectivity panel also revealed that, compared to the three other indirubins, 7BIO is a poor kinase inhibitor.…”

Section: Different Bromoindirubins Display Different Selectivities Fomentioning

confidence: 99%

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7-Bromoindirubin-3′-oxime induces caspase-independent cell death

Ribas

Bettayeb²,

Ferandin³

et al. 2006

Oncogene

102

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Section: Discussionmentioning

confidence: 99%

Section: Different Bromoindirubins Display Different Selectivities Fomentioning

confidence: 99%

7-Bromoindirubin-3′-oxime induces caspase-independent cell death

Ribas

Bettayeb²,

Ferandin³

et al. 2006

Oncogene

102

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“…Indirubin and particularly indirubin derivatives such as indirubin-3 0 -monoxime and indirubin-5-sulfonate, which have low toxicity, have been considered as anticancer agents (Hoessel et al, 1999). Indirubin and its derivatives have been described as selective inhibitors of cyclin-dependent kinases (CDKs) such as CDK1/ cyclin B, CDK2/cyclin A, CDK2/cyclin E and CDK5/ p25 (Hoessel et al, 1999;Davies et al, 2001;Marko et al, 2001;Jautelat et al, 2005). It has been reported that these compounds are able to inhibit the proliferation of a variety of cultured cell types by a block in the G1/S or the G2/M phase of the cell cycle.…”

Section: Introductionmentioning

confidence: 99%

Indirubin-3′-monoxime inhibits autophosphorylation of FGFR1 and stimulates ERK1/2 activity via p38 MAPK

et al. 2007

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Indirubin-3 0 -monoxime is a derivative of the bis-indole alkaloid indirubin, an active ingredient of a traditional Chinese medical preparation that exhibits anti-inflammatory and anti-leukemic activities. Indirubin-3 0 -monoxime is mainly recognized as an inhibitor of cyclin-dependent kinases (CDKs) and glycogen synthase kinase-3. It inhibits proliferation of cultured cells, mainly through arresting the cells in the G1/S or G2/M phase of the cell cycle. Here, we report that indirubin-3 0 -monoxime is able to inhibit proliferation of NIH/3T3 cells by specifically inhibiting autophosphorylation of fibroblast growth factor receptor 1 (FGFR1), blocking in this way the receptormediated cell signaling. Indirubin-3 0 -monoxime inhibits the activity of FGFR1 at a concentration lower than that required for inhibition of phosphorylation of CDK2 and retinoblastoma protein and cell proliferation stimulated by fetal calf serum. The ability of indirubin-3 0 -monoxime to inhibit FGFR1 signaling was similar to that of the FGFR1 inhibitor SU5402. In addition, we found that indirubin-3 0 -monoxime activates long-term p38 mitogen-activated protein kinase activity, which stimulates extracellular signal-regulated kinase 1/2 in a way unrelated to the activity of FGFR1. Furthermore, we show that indirubin-3 0 -monoxime can inhibit proliferation of the myeloid leukemia cell line KG-1a through inhibition of the activity of the FGFR1 tyrosine kinase. The data presented here demonstrate previously unknown activities of indirubin-3 0 -monoxime that may have clinical implications.

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“…Except for two, all have the indolone lactam group bound to the gk+1 and gk+3 residues. 60 There is one structure of CSNK1 kinase that shows the NH and carbonyl of the lactam pointed toward the hinge but has the molecule flipped 180°so the carbonyl is facing the gatekeeper region while the N(H) is close to the gk+3 NH. It is quite possible that this structure is bound in a different tautomeric form.…”

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confidence: 99%