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. Author manuscript; available in PMC: 2021 Dec 8.
Published in final edited form as: Clin Cancer Res. 2021 Feb 4;27(9):2648–2662. doi: 10.1158/1078-0432.CCR-20-2961

Figure 2. Identification of a novel dual p38 and NLK inhibitor VX-702, and its therapeutic effect to tamoxifen treatment in vitro.

Figure 2.

(a) Heatmap of “hot-spot” drug-kinase assay identifying VX-702 as a potent dual p38 MAPK and NLK inhibitor with exclusive activity against p38 MAPKs and NLK. The percentage of kinase activity inhibition is shown in the red color scale. (b) Bar chart showing the inhibition efficacy of VX-702 over a panel of 300 kinases based on the same dataset as in A. (c) In vitro kinase assay using recombinant NLK protein and MBP as the substrate in the presence or absence of VX-702 treatment. (d) In vitro kinase assay for V5-NLK immuno-precipitated from VX-702 treated MCF7 cells using MBP as the substrate. In order to maintain the inhibition of NLK, the immunoprecipitation product was incubated in different doses of VX-702 throughout the in vitro kinase assay process. (e) The survival fraction of MCF7-TamR breast cancer cells and MCF10A non-cancerous breast epithelial cells following treatment with different doses of VX-702 for 7 days; 0.5 μM was determined as the effective concentration in vitro. (f) The therapeutic effect of VX-702 on 4-OH tamoxifen treatment in primary and acquired tamoxifen resistant breast cancer cell lines. The assays were carried out for 7 days under estrogen deprived condition. (g) Induction of ectopic NLK expression rescues the therapeutic effect of VX-702 to tamoxifen treatment in the MCF7-TamR and T47D-TamR cells. ***P<0.001 (based on two-way ANOVA). The error bars represent the standard deviations.