Indirubin-3′-monoxime, a derivative of a Chinese antileukemia medicine, inhibits P-TEFb function and HIV-1 replication

Heredia, Alonso; Davis, Charles E.; Bamba, Douty; Le, Nhut; Gwarzo, Muhammad Yalwa; Sadowska, Mariola; Gallo, Robert C.; Redfield, Robert

doi:10.1097/01.aids.0000194805.74293.11

Cited by 55 publications

(55 citation statements)

References 33 publications

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“…It has also been shown that the indirubin derivatives indirubin-5-sulfonate and indirubin-3 0 -monoxime bind to the CDK2 adenosine triphosphate-binding site and in this way inhibit the kinase activity (Hoessel et al, 1999;Davies et al, 2001). Furthermore, indirubin-3 0 -monoxime, but not indirubin, was able to inhibit CDK9 in a cell-free kinase assay and to inhibit replication of HIV-1 in blood mononuclear cells and macrophages (Heredia et al, 2005). Additionally, it was recently reported that indirubin derivatives were able to block Stat3 signaling by inhibiting the Src kinase activity and in this way induce apoptosis in human cancer cells (Nam et al, 2005), and also, bind to and inhibit glycogen synthetase kinase-3 (Leclerc et al, 2001;Polychronopoulos et al, 2004), aryl hydrocarbon receptor (Adachi et al, 2001), muscle glycogen phosphorylase b (Kosmopoulou et al, 2004) and c-Jun NH2-terminal kinase (JNK) (Xie et al, 2004).…”

Section: Introductionmentioning

confidence: 92%

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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Section: Introductionmentioning

confidence: 92%

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

et al. 2007

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“…Several compounds that possess anti-HIV activity in vitro, such as quinoline derivatives TR-87, K-37, and WM5, stilbene derivative CGA137053, and substituted purines (5,27,30,56,74), have been identified as inhibiting Tat transactivity by obstructing Tat/TAR binding, whereas others, such as flavopiridol, roscovitine, and indirubin-3Ј-monoxime (12,28,68), were shown to inhibit Tat transactivity by targeting the p-TEFb component CDK9. Based on our finding, BPRHIV001 could inhibit Tat function through modulating the PI3K/Akt pathway, which has been shown to be essential in HIV replication (17,23).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of HIV-1 Tat-Mediated Transcription by a Coumarin Derivative, BPRHIV001, through the Akt Pathway

Lin

et al. 2011

J Virol

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The human immunodeficiency virus type 1 (HIV-1)-encoded RNA-binding protein Tat is known to play an essential role in viral gene expression. In the search for novel compounds to inhibit Tat transactivity, one coumarin derivative, BPRHIV001, was identified, with a 50% effective concentration (EC 50 ) against HIV-1 at 1.3 nM. BPRHIV001 is likely to exert its effects at the stage after initiation of RNAPII elongation since Tat protein expression and the assembly of the Tat/P-TEFb complex remained unchanged. Next, a reduction of the p300 protein level, known to modulate Tat function through acetylation, was observed upon BPRHIV001 treatment, while the p300 mRNA level was unaffected. A concordant reduction of phosphorylated Akt, which was shown to be closely related to p300 stability, was observed in the presence of BPRHIV001 and was accompanied by a decrease of phosphorylated PDPK1, a well-known Akt activator. Furthermore, the docking analysis revealed that the reduced PDPK1 phosphorylation likely resulted from the allosteric effect of interaction between BPRHIV001 and PDPK1. With strong synergistic effects with current reverse transcriptase inhibitors, BPRHIV001 has the potential to become a promising lead compound for the development of a novel therapeutic agent against HIV-1 infection.

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“…Seventy-five structurally diverse CDK9 inhibitors were collected from published literatures [2,3,[7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26]. The activities of these inhibitors were expressed as IC 50 values for CDK9 inhibition, which range from 2 to 30,000 nM.…”

Section: The Data Setmentioning

confidence: 99%

Generation and validation of the first predictive pharmacophore model for cyclin-dependent kinase 9 inhibitors

Fang

Xiao

Guo

2011

Journal of Molecular Graphics and Modelling

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Indirubin-3′-monoxime, a derivative of a Chinese antileukemia medicine, inhibits P-TEFb function and HIV-1 replication

Cited by 55 publications

References 33 publications

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

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

Inhibition of HIV-1 Tat-Mediated Transcription by a Coumarin Derivative, BPRHIV001, through the Akt Pathway

Generation and validation of the first predictive pharmacophore model for cyclin-dependent kinase 9 inhibitors

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