The pharmaceutical industry faces unprecedented challenges, with late-stage clinical failures mainly due to poor target validation (TV) and lack of predictive biomarkers. Target-directed drug discovery (TDD) and phenotypic drug discovery (PDD) are complementary strategies, but classic PDD's intrinsic probability of technical success (pTS) is underestimated, and 'neoclassic' PDD (blending physiologically relevant biological systems with modern assay technologies) is not widely used in Pharma due to concerns about assay performance, structure-activity relationships (SAR), chemoinformatics applicability, etc. This study addresses these issues using an angiogenesis assay incorporating a coculture of primary human endothelial and stromal progenitor cells. Results indicate phenotypic assays can be statistically robust, identify novel compound scaffolds via chemoinformatics-enabled hit expansion, and provide evidence of SAR. Novel molecular targets important to angiogenesis—acetyl Co-A carboxylase (ACC) and a protein related to cellular β-secretase (β-sec) activity—were identified, demonstrating PDD's ability to agnostically test multiple biologically relevant pathways. Phenotypic actives were structurally and mechanistically differentiated from antiangiogenic standard of care (SOC) agents and showed in vivo activity. We conclude PDD complements TDD, mitigates TV risks, and has the potential to enhance innovation in drug discovery.