In this study, we developed a hit identification pipeline, i.e. Pocket Crafter, that leverages a 3D generative chemistry method to generate novel active molecules as early hits. We utilized this pipeline to propose hit molecules for WDR5 in the 3D space, specifically targeting its WBM pocket that interacts with the oncogenic factor MYC. To evaluate the potential hits, we conducted in vitro biological assays on WDR5 and identified a novel chemical series exhibiting clustered activity. This chemical series demonstrated the ability to disrupt WDR5-MYC interaction in the biochemical assay and acted as binders to WDR5 in the biophysical assay. Together with this case study, our work represents an end-to-end 3D generative chemistry workflow as a viable approach for discovering novel active compounds in the early drug discovery phase.