Ainsliadimer A selectively inhibits IKKα/β by covalently binding a conserved cysteine

Dong, Ting; Li, Chao; Wang, Xing; Dian, Longyang; Zhang, Xiuguo; Li, Lin; Chen, She; Cao, R.; Li, L i; Huang, Niu; He, Sudan; Lei, Xiaoguang

doi:10.1038/ncomms7522

Cited by 105 publications

(95 citation statements)

References 38 publications

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“…To avoid potential systemic exposure, an inhaled IKK-b inhibitor (PF-104) was developed to inhibit neutrophilic lung inflammation induced by inhaled endotoxin in mice (Sommers et al, 2009). Ainsliadimer-A is found in a Chinese herbal product that has been described as a potent and selective inhibitor of IKKa/b, thus inhibiting the classic and alternative pathways of NF-kB (Dong et al, 2015). It inhibits the release of inflammatory cytokines after LPS injection in mice, so has potential as an anti-inflammatory drug.…”

Section: B Inhibitorsmentioning

confidence: 99%

Kinases as Novel Therapeutic Targets in Asthma and Chronic Obstructive Pulmonary Disease

Barnes

2016

Pharmacol Rev

103

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Section: B Inhibitorsmentioning

confidence: 99%

Kinases as Novel Therapeutic Targets in Asthma and Chronic Obstructive Pulmonary Disease

Barnes

2016

Pharmacol Rev

103

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“…The drug molecules are connected to biocompatible inert resin (magnetic beads or agarose gel) through chemical reaction. The target protein of the drug molecule was determined by electrophoresis, purification and high resolution mass spectrometry [42][43][44][45][46]. Using this strategy, a series of targets for active components of TCM have been successfully identified.…”

Section: Discussionmentioning

confidence: 99%

Elucidating Direct Kinase Targets of Compound Danshen Dropping Pills Employing Archived Data and Prediction Models

Wang¹,

Liang

Zhao³

et al. 2020

Preprint

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The research on the direct target of traditional Chinese medicine (TCM) is the key to study the mechanism and material basis of TCM, but there is still no effective technical methods at present. For Compound Danshen dropping pills (CDDP), there is no report about its direct targets. In this study, the direct targets of CDDP were studied for the first time, especially focusing on the protein kinase family, which plays causal roles in a variety of human disease. Firstly, the literature database of CDDP was constructed by literature retrieval, and the important components contained in CDDP were extracted. Secondly, the potential direct targets of important components was obtained through querying public database and predicted by Multi-voting SEA algorithm. Then, the KinomeX system was used to predict and to filter the potential kinase targets of CDDP. Finally, the experimental verification was carried out. In total, 30 active kinase targets was obtained at 25 µg/ml concentration of CDDP, and 9 dosedependent targets were obtained at 250 µg/ml concentration of CDDP. This is an efficient and accurate strategy by integrating the targets recorded in several public databases and the targets calculated by two in silico modelling approaches predict potential direct targets of TCM, which can lay an important foundation for the study of the mechanism and material basis of them, promoting the modernization of TCM. Predictive Models for Fast and Effective Profiling of Kinase Inhibitors. J Chem Inf Model, 2016. 56(5): p. 895-905. 30.Lapins, M. and J.E. Wikberg, Kinome-wide interaction modelling using alignment-based and alignment-independent approaches for kinase description and linear and non-linear data analysis techniques. 11(1): p. 339-0.

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“…Inhibitors that selectively bind to the conserved Cys-46 are expected to inhibit all the pathways that result in NFκB activation. 30, 31 …”

Section: Molecular Modeling Analysismentioning

confidence: 99%

Succinamide derivatives of melampomagnolide B and their anti-cancer activities

Janganati

Ponder

Thakkar

et al. 2017

Bioorganic & Medicinal Chemistry

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A series of succinamide derivatives of melampomagnolide B have been synthesized by coupling MMB monosuccinate (2) with various heterocyclic amines to afford compounds 3a–3l. MMB monosuccinate was also reacted with terminal diaminoalkanes to afford dimeric succinamido analogs of MMB (4a–4h). These succinamide analogs of MMB were evaluated for their anti-cancer activity against a panel of sixty human cancer cell lines. Analogs 3d–3i and dimers 4f–4g exhibited promising anti-cancer activity with GI50 values ranging from 0.28-33.5 μM against most of the cell lines in the panel. The dimeric analogs 4f and 4g were identified as lead compounds with GI50 values in the nanomolar range (GI50 = 280–980 nM) against several cell lines in the panel; i.e. leukemia cell lines CCRF-CEM, HL-60(TB), K-562, MOLT-4, RPMI-8226 and SR; and solid tumor cell lines NCI-H522 (non-small cell lung cancer), SW-620 and HCT-116 (colon cancer), LOX IMVI (melanoma), RXF 393 (renal cancer), and MCF7, BT-549 and MDA-MB-468 (breast cancer). Succinamide analogs 3a, 3c–3l and 4b–4h were also evaluated for their apoptotic activity against M9-ENL1 acute myelogenous leukemia cells; compounds 3h–3j and 4g were equipotent with parthenolide, exhibiting LC50 values in the range 4.1–8.1 μM. Molecular docking studies indicate that these molecules interact covalently with the highly conserved Cys-46 residue of the N-terminal lobe (1–109) of human IKKβ to inhibit the NFκB transcription factor complex, resulting in down-regulation of anti-apoptotic genes under NFκB control.

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Ainsliadimer A selectively inhibits IKKα/β by covalently binding a conserved cysteine

Cited by 105 publications

References 38 publications

Kinases as Novel Therapeutic Targets in Asthma and Chronic Obstructive Pulmonary Disease

Kinases as Novel Therapeutic Targets in Asthma and Chronic Obstructive Pulmonary Disease

Elucidating Direct Kinase Targets of Compound Danshen Dropping Pills Employing Archived Data and Prediction Models

Succinamide derivatives of melampomagnolide B and their anti-cancer activities

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