SynergyFinder: a web application for analyzing drug combination dose–response matrix data

Ianevski, Aleksandr; He, Liye; Aittokallio, Tero; Tang, Jing

doi:10.1093/bioinformatics/btx162

Cited by 436 publications

(286 citation statements)

References 8 publications

(9 reference statements)

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“…2A). The Loewe additive model and the Bliss independent model (Malyutina et al, 2019) were used to analyse the interaction of the two compounds using SynergyFinder (Ianevski et al, 2017). Remdesivir and emetine in combination yielded a Loewe synergy score of 0.306 (Fig.…”

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confidence: 99%

“…The percentage of viral inhibition was normalized based on viral load in logarithm scale (log 10 RNA copies/mL), using the maximal viral RNA copies with no drug controls as 0% inhibition and the minimal RNA copies determined at 50 μM remdesivir as references. (B) The three-dimensional interaction landscapes of remdesivir and emetine were generated by SynergyFinder(Ianevski et al, 2017) based on (B) the Loewe additive model and (C) the Bliss independence model. Red colour indicates synergy while the green colour indicates antagonism of the two drugs.…”

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Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro

et al. 2020

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An escalating pandemic by the novel SARS-CoV-2 virus is impacting global health and effective therapeutic options are urgently needed. We evaluated the in vitro antiviral effect of compounds that were previously reported to inhibit coronavirus replication and compounds that are currently under evaluation in clinical trials for SARS-CoV-2 patients. We report the antiviral effect of remdesivir, lopinavir, homorringtonine, and emetine against SARS-CoV-2 virus in Vero E6 cells with the estimated 50% effective concentration at 23.15 μM, 26.63 μM, 2.55 μM and 0.46 μM, respectively. Ribavirin or favipiravir that are currently evaluated under clinical trials showed no inhibition at 100 μM. Synergy between remdesivir and emetine was observed, and remdesivir at 6.25 μM in combination with emetine at 0.195 μM may achieve 64.9% inhibition in viral yield. Combinational therapy may help to reduce the effective concentration of compounds below the therapeutic plasma concentrations and provide better clinical benefits.

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Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro

et al. 2020

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“…Therefore, for each drug combination, SynToxProfiler first calculates a normalized volume under dose-response surface to quantify combination efficacy based on dose-response measurements on diseased cells, e.g., patient-derived primary cells (see S1 Fig). Then, the combination synergy between each drug pair is estimated using one of the synergy scoring models: Highest Single-Agent [5], Bliss independence [6], Loewe additivity [7], or Zero Interaction Potency (ZIP) [8], as implemented in the SynergyFinder webtool [21]. Normalized volume under the dose-synergy surface is utilized to quantify final combination synergy score (S1 Fig). Next, using the measurements on control cells, if available, the normalized volume under dose-response matrix is calculated to estimate combination toxicity (S1 Fig). Finally, SynToxProfiler ranks the drug combinations based on integrated combination synergy, toxicity and efficacy (STE) score.…”

Section: Syntoxprofiler Workflowmentioning

confidence: 99%

“…The efficacy, toxicity, and synergy matrices for the top drug pairs selected based on the highest STE score (clomiphene citrate and sertraline HCL, upper panel) and the highest synergy score (toremifene citrate and apilimod, lower panel). The synergy was calculated using the ZIP model implemented in SynergyFinder[21]. The square with dotted line denotes the 3x3 concentration range with the most synergistic area in the dose-response matrix.https://doi.org/10.1371/journal.pcbi.1007604.g003…”

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SynToxProfiler: An interactive analysis of drug combination synergy, toxicity and efficacy

et al. 2020

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Drug combinations are becoming a standard treatment of many complex diseases due to their capability to overcome resistance to monotherapy. In the current preclinical drug combination screening, the top combinations for further study are often selected based on synergy alone, without considering the combination efficacy and toxicity effects, even though these are critical determinants for the clinical success of a therapy. To promote the prioritization of drug combinations based on integrated analysis of synergy, efficacy and toxicity profiles, we implemented a web-based open-source tool, SynToxProfiler (Synergy-Toxicity-Profiler). When applied to 20 anti-cancer drug combinations tested both in healthy control and T-cell prolymphocytic leukemia (T-PLL) patient cells, as well as to 77 anti-viral drug pairs tested in Huh7 liver cell line with and without Ebola virus infection, SynToxProfiler prioritized as top hits those synergistic drug pairs that showed higher selective efficacy (difference between efficacy and toxicity), which offers an improved likelihood for clinical success. Author summaryHigh-throughput combinatorial screening is an established approach to identify candidate drug combinations to be further developed as safe and effective treatment options for many diseases, such as various types of cancers, bacterial, malarial, and viral infections. The selection of top performing drug combinations for further development is an important step for the success of the screen, where not only the synergy but also selective efficacy and potential toxicity of the drug pairs should be critically assessed. Currently, there is no method available for this; therefore, we developed SynToxProfiler tool, which was demonstrated in two different application cases to prioritize synergistic drug pairs with higher efficacy and lower toxicity as top hits, providing thus an increased likelihood for their clinical success.PLOS Computational Biology | https://doi.

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“…Titration curves and IC50 values were generated using GraphPad Prism software. Dose-response data of drug combinations were analyzed with the SynergyFinder R package for synergism 66 . Synergy scores were calculated across all concentration combinations using Loewe or Bliss models.…”

Section: Chip Quantitative Pcr (Chip-qpcr)mentioning

confidence: 99%

Elevatedde novofatty acid biosynthesis gene expression promotes melanoma cell survival and drug resistance

2018

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Elevated de novo fatty acid biosynthesis (DNFA) is a hallmark adaptation in many cancers that supports survival, proliferation, and metastasis. Here we elucidate previously unexplored aspects of transcription regulation and clinical relevance of DNFA in melanomas. We show that elevated expression of DNFA genes is characteristic of many tumor types and correlates with poor prognosis. Elevated DNFA gene expression depends on transcription factor SREBP1 in multiple melanoma cell lines. SREBP1 predominantly binds to the transcription start sites of DNFA genes, directly regulating transcription via RNA polymerase II recruitment and productive elongation. We find that SREBP1-regulated DNFA represents an intrinsic survival mechanism in melanoma cells, regardless of proliferative state and oncogenic mutation status. Indeed, malignant melanoma cells exhibit elevated DNFA gene expression after pro-survival signaling pathways are blocked (e.g. by the BRAF inhibitor vemurafenib). Altogether, these results implicate SREBP1 and DNFA enzymes as enticing therapeutic targets in melanomas.

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SynergyFinder: a web application for analyzing drug combination dose–response matrix data

Cited by 436 publications

References 8 publications

Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro

Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro

SynToxProfiler: An interactive analysis of drug combination synergy, toxicity and efficacy

Elevatedde novofatty acid biosynthesis gene expression promotes melanoma cell survival and drug resistance

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