<b>Objectives:</b> <i>CTNNB1</i> is a gene that codes for the b-catenin protein, involved in the Wnt/b-catenin pathway and associated with endometrial cancer (EC) recurrence. Biomarker-driven treatment strategies are an important avenue of research. M08502 is a novel pan-CLK inhibitor that targets mRNA splicing and is optimized for Wnt pathway inhibition. We aimed to evaluate the combination SM08502 and paclitaxel in the preclinical setting. <b>Methods:</b> <i>In vitro</i> and <i>in vivo</i> models were used to evaluate the combination SM08502 and paclitaxel in four EC cell lines. We studied two <i>CTNNB1</i> mutant cell lines (HEC 265, SNGM), one <i>CTNNB1</i> wildtype cell line (Ishikawa), and one <i>CTNNB1</i>-S33Y mutant cell line created via retroviral transduction (Ishikawa-S33Y). Dose-response curves and 50% inhibitory concentrations (IC50) were determined based on cell viability. Apoptosis was evaluated via Annexin V/propidium iodide (PI). TCF transcriptional activity was determined via TOP/FOP reporter assay. Combination index (CI) evaluation for synergy was evaluated using CompuSyn programming. Tumor-bearing athymic nude mice were treated with vehicle (PBS), daily SM08502 (orally, 12.5 mg/kg), weekly paclitaxel (10 mg/kg), or in combination with daily SM08502/weekly paclitaxel. Tumors were evaluated with immunohistochemistry for proliferation (Ki67). <b>Results:</b> SM08502 is an active single-agent therapy with IC50 in the nanomolar range for all four EC cell lines. Compared to control, 1200 nM SM08502 significantly induces apoptosis in Ishikawa (7.3% vs 16.63% AnnexinV/PI+, p < 0.0001), HEC265 (12.47% vs 39.9% AnnexinV/PI+, p < 0.0001), and SNGM (19.93% vs 67.3%, p < 0.0001), but not Ishikawa-S33Y. Compared to control, single-agent SM08502 (800 nM) significantly decreases TCF transcriptional activity in all four cell lines (HEC265: -93.9 %TCF activity, p < 0.0001; SNGM: -45.9%, p=0.03; Ishikawa-S33Y: -93.3%, p < 0.0001; Ishikawa: -93.1%, p < 0.0001). HEC265, Ishikawa-S33Y and Ishikawa cells all demonstrated a synergy with combination paclitaxel with CI <1. SNGM cells demonstrate an additive effect at all dose levels combined with paclitaxel. Ishikawa demonstrated significantly lower tumor volumes of combination versus SM08502 alone (Repeated Measures one-way ANOVA, p=0.04), but not versus paclitaxel alone. HEC265, SNGM, and Ishikawa-S33Y tumors all had significantly lower tumor volumes with combination of SM08502 and paclitaxel compared to single-agent paclitaxel (Repeated Measures one-way ANOVA, p=0.01, 0.004, and 0.0008, respectively) or single-agent SM08502 (Repeated Measures one-way ANOVA, p=0.002, 0.005, and 0.01, respectively) alone. <b>Conclusions:</b> TCF transcriptional Wnt inhibition combined with paclitaxel has a synergistic effect <i>in vitro</i> and inhibits tumor progression in four endometrial cancer models. Human clinical trials are warranted to evaluate this combination strategy.