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We established a spheroid-based sprouting assay using human lymphatic endothelial cells to mimic lymphangiogenesis and performed a phenotypic screen of focused libraries of epigenetic regulators, kinase inhibitors, and stem cell modulators. Automated imaging and quantitative analysis identified several kinase inhibitors, previously characterized as GSK3\u00df inhibitors, as prolymphangiogenic regulators. Among them, the most potent was kenpaullone, which activated the same canonical prolymphangiogenic ERK pathway as VEGF-C, but induced a distinct transcriptional response in treated spheroids. Using kenpaullone-derived chemical probes and target-validation approaches, we identified MAP4K4 as a molecular target mediating the prolymphangiogenic effect observed. 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