Fragment-based drug discovery (FBDD) has proven to be an effective method in finding therapeutics for difficult drug targets. We present a cutting-edge approach to identify active molecules in purchasable chemical space. This method begins with four small-molecule fragments that interact with protein kinase A (PKA). A template-based docking screen using Enamine’s REAL Space database was then conducted. Out of 106 selected compounds, 93 were synthesized and 40 showed activity in validation assays, with the most promising having a 13,500-fold increase in affinity. Crystal structures for six of the strongest binders were quickly obtained to confirm their binding mode. With a success-rate of 40%, this novel fragment-to-hit approach was executed in only 9 weeks. The results challenge the standard fragment prescreening methods as the standard filters used in thermal shift assays would have overlooked the initial fragments.