Designing transient binding drugs: A new concept for drug discovery

Ohlson, Sten

doi:10.1016/j.drudis.2008.02.001

Cited by 86 publications

(69 citation statements)

References 43 publications

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“…K D values between the FapC fibrils and pyocyanin, PQS, and 3-oxo-C12-HSL were 400, 250, and 100 M, respectively. These values and the box-shaped interaction kinetics indicate that they have transient binding to the fibrils (45). Metabolite binding was therefore similar to that of ThT, which is commonly used as a diagnostic tool for amyloids because of its altered spectral properties upon amyloid binding (46).…”

Section: Qs Molecules Display Transient Binding To Fapc Fibrils-mentioning

confidence: 63%

Functional Amyloids Keep Quorum-sensing Molecules in Check

Seviour

Hansen

Yang

et al. 2015

Journal of Biological Chemistry

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Section: Qs Molecules Display Transient Binding To Fapc Fibrils-mentioning

confidence: 63%

Functional Amyloids Keep Quorum-sensing Molecules in Check

Seviour

Hansen

Yang

et al. 2015

Journal of Biological Chemistry

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“…However, the traditional trial-and-error methods used to identify active compounds from numerous herbal compounds in TCM are time-consuming and labor intensive. Additionally, modern high-throughput screening assays have limitations in identifying the active compounds from TCM herbs because many herbal compounds feature weak or moderate binding to multiple targets [4,5] , even though TCM formulas have been shown to inhibit tumors in clinical settings [6] . Therefore, research regarding the identification of potentially active compounds from TCMs might require novel approaches, such as emerging TCM network pharmacology [7,8] .…”

Section: Introductionmentioning

confidence: 99%

Identification of the anti-tumor activity and mechanisms of nuciferine through a network pharmacology approach

et al. 2016

Acta Pharmacol Sin

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Aim: Nuciferine is an aporphine alkaloid extracted from lotus leaves, which is a raw material in Chinese medicinal herb for weight loss. In this study we used a network pharmacology approach to identify the anti-tumor activity of nuciferine and the underlying mechanisms. Methods: The pharmacological activities and mechanisms of nuciferine were identified through target profile prediction, clustering analysis and functional enrichment analysis using our traditional Chinese medicine (TCM) network pharmacology platform. The antitumor activity of nuciferine was validated by in vitro and in vivo experiments. The anti-tumor mechanisms of nuciferine were predicted through network target analysis and verified by in vitro experiments. Results: The nuciferine target profile was enriched with signaling pathways and biological functions, including "regulation of lipase activity", "response to nicotine" and "regulation of cell proliferation". Target profile clustering results suggested that nuciferine to exert anti-tumor effect. In experimental validation, nuciferine (0.8 mg/mL) markedly inhibited the viability of human neuroblastoma SY5Y cells and mouse colorectal cancer CT26 cells in vitro, and nuciferine (0.05 mg/mL) significantly suppressed the invasion of 6 cancer cell lines in vitro. Intraperitoneal injection of nuciferine (9.5 mg/mL, ip, 3 times a week for 3 weeks) significantly decreased the weight of SY5Y and CT26 tumor xenografts in nude mice. Network target analysis and experimental validation in SY5Y and CT26 cells showed that the anti-tumor effect of nuciferine was mediated through inhibiting the PI3K-AKT signaling pathway and IL-1 levels in SY5Y and CT26 cells. Conclusion: By using a TCM network pharmacology method, nuciferine is identified as an anti-tumor agent against human neuroblastoma and mouse colorectal cancer in vitro and in vivo, through inhibiting the PI3K-AKT signaling pathways and IL-1 levels.

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“…An illustrative example of a "promiscuous" drug is the anti-cancer agent Gleevec1, which shows promise in the treatment of leukemia (32). To our knowledge, CDBT is the first chemical agent that targets both tubulin and HSP90 in P-gp over-expressing H460 TaxR cells.…”

Section: The Molecular Mechanism For Cdbt's Cancer-killing Effectsmentioning

confidence: 99%

“…Multi-targeting therapy can be realized as a multi-component drug, which is either a mixture of different molecules that selectively act on multiple targets or a "promiscuous" drug, which is a single molecule that selectively targets multiple targets simultaneously. The value of combination therapy (31) and "promiscuous" drugs (32) have been documented in the treatment of cancer.…”

Section: The Molecular Mechanism For Cdbt's Cancer-killing Effectsmentioning

confidence: 99%

P-Glycoprotein-Evading Anti-tumor Activity of a Novel Tubulin and HSP90 Dual Inhibitor in a Non-small-cell Lung Cancer Model

et al. 2014

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Abstract. P-glycoprotein (P-gp)-induced drug resistance is a major road block for successful cancer chemotherapy. Through phenotypic screening, the compound 2-(2-chlorophenylimino)-5-(4-dimethylaminobenzylidene)thiazolidin-4-one (CDBT) was discovered to have potent antitumor activity in P-gp over-expressing drug-resistant non-small-cell lung cancer (NSCLC) H460 TaxR cells. Here, we report mechanistic investigations of the P-gp-evading anti-tumor activity of CDBT. CDBT is evidently not a P-gp substrate and escapes the P-gp efflux pump. As a novel microtubule and heat shock protein 90 (HSP90) dual targeting inhibitor, CDBT causes the destabilization of microtubules and degradation of HSP90 client proteins CRAF-1 and ERBB2, resulting in cell cycle arrest at the G2/M phase and apoptosis. Furthermore, CDBT effectively inhibits tumor growth by 60.4% relative to the vehicle control after intraperitoneal administration at 30 mg/kg for 11 days and shows no toxicity in normal tissues in the NSCLC H460 TaxR xenograft mouse model. Our data suggest a novel drug discovery strategy to combat P-gp over-expressing drug-resistant NSCLC cancer cells with a single therapeutic agent.[Supplementary materials: available only at http://dx

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Designing transient binding drugs: A new concept for drug discovery

Cited by 86 publications

References 43 publications

Functional Amyloids Keep Quorum-sensing Molecules in Check

Functional Amyloids Keep Quorum-sensing Molecules in Check

Identification of the anti-tumor activity and mechanisms of nuciferine through a network pharmacology approach

P-Glycoprotein-Evading Anti-tumor Activity of a Novel Tubulin and HSP90 Dual Inhibitor in a Non-small-cell Lung Cancer Model

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