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  • KX2-391 br where x is the observed number of TNBC

    2020-03-17


    where x is the observed number of TNBC proteins targeted by a given natural product, m is the mean number of TNBC proteins targeted by a given natural product during 100,000 permuta-tions, and s is the SD.
    We computed a list of candidate natural products (see the STAR Methods) ranked by decreasing Z score through search-ing 150 known TNBC proteins (Data S1) derived from large-scale genetic and genomic studies within a network of 38,220 compound-protein interactions (Data S2). To evaluate the per-formance of the computational model, we retrieved published indications from PubMed for 706 natural products predicted to be anti-TNBC (Data S1). The area under the receiver oper-ating characteristic curve is 71.9%, suggesting a reasonable accuracy in predicting therapeutic agents in treating TNBC (Figure 1A).
    Among the 706 natural products, we computationally identified 148 as significantly anti-TNBC (adjusted p value [q] < 10 5). Chemical clustering groups them into 10 clusters. Cluster 5 (named flavonoids, n = 39) is the largest (Figure 1B). Figure 1C displays the predicted anti-TNBC data for 39 flavonoids. We next used subject KX2-391 expertise based on: (1) removing flavonoids with potential cytochrome p450 (CYP450) inhibition (CYP450 inhibitors involving in the high risk of adverse drug-drug interactions [Lynch and Price, 2007]) or having preclinical toxicity predicted by admetSAR (Cheng et al., 2012a); (2) novelty of prediction through exclusion of flavonoids with literature-reported anti-TNBC effects; and (3) strength of the systems pharmacology-based prediction (a higher Z score in Data S1). Applying these criteria resulted in wogonoside (q < 10 5, z = 12.7), one of the major active flavones in Scutellaria baicalensis Georgi, as the best candidate (Data S1). We thus selected wogo-noside and tested its antitumor effect in TNBC.
    A nude mouse model bearing transplanted MDA-MB-231 tumor was used to evaluate anti-TNBC effect of wogonoside (Figure 1D) in vivo. The resected tumor weight was reduced to 55.47% by wogonoside (80 mg/kg) compared with the untreated group (Figure 1E). In addition, wogonoside significantly sup-presses growth of MDA-MB-231 cell xenografts (Figure 1F), sug-gesting that wogonoside restrains the growth of transplanted MDA-MB-231 tumor in nude mouse model.
    Please cite this article in press as: Huang et al., A Systems Pharmacology Approach Uncovers Wogonoside as an Angiogenesis Inhibitor of Triple-Negative Breast Cancer by Targeting Hedgehog Signaling, Cell Chemical Biology (2019), https://doi.org/10.1016/j.chembiol.2019.05.004
    Figure 1. A Diagram Illustrating Systems Pharmacology-Based Prediction of Antitumor Effects of Wogonoside in Triple-Negative Breast Cancer
    (A) An in silico model for predicting anti-TNBC indications for natural products by integrating the drug-target network and experimentally validated functional genes in TNBC. The performance of the in silico model was evaluated using receiver operating characteristic (ROC) curve. The area under ROC curve (AUC) was shown. (B) The chemical structure clustering analysis for 148 natural products having the significantly predicted anti-TNBC indications (q < 10 5).
    (C) Circos plot (Circo v.0.69) representing the predicted anti-TNBC indications (q < 10 5) for 24 steroids and 39 flavonoids. The predicted q values with corresponding Z score are exhibited as connected lines (edges). Natural products with previously published experimental data in TNBC are highlighted in bold font. Wogonoside was selected for experimental validation using subject matter expertise based on a combination of factors (see Data S1 for references).
    (D) Effect of wogonoside on MDA-MB-231 tumor growth in nude mice.
    (E) The tumor weight of control and wogonoside treatment group (n = 7) was measured after 15 days treatment.
    (F) The tumor volume of control and wogonoside treatment group (n = 7) was measured every 3 days. The comparisons were made relative to the control group and the significance of the difference is indicated as *p < 0.05 and **p < 0.01.