Multiple ligand efficient fragment inhibitors of protein kinase B were identified through a combined in silico compound screen and high-throughput crystallographic analysis of protein-ligand structures. A well-validated apo-PKB-PKA chimeric protein provided a convenient platform for high-throughput crystallography by soaking of inhibitors, and a method for the determination of PKB-ligand structures was developed to support inhibitor development. Pyrazole and azaindole fragment hits with micromolar activity were rapidly progressed to nanomolar inhibitors of PKB with activity in cells using crystallographic analysis of inhibitor binding modes to guide medicinal chemistry. Compounds with selectivity for PKB over PKA and other kinases were identified by this approach, resulting in potent inhibitors with in vivo activity through both oral and systemic administration, and suitable for further development.