Fig. 4. Overview illustrates the synthesized and evaluated library of covalent-allosteric Akt inhibitors. Phenylamide-, benzo[d]imidazolone- and urea-based derivates gain insights into the structure–activity-relationships. The diversification of scaffolds and resulted in novel binding modes with different preference in labeling Cys296 and Cys310. Phenylamide-based inhibitors broadened chemical space and showed improved metabolic stability for 30b. Small substitutions of the benzo[d]imidazolone-core allowed a gain of cellular potency. Urea-based inhibitor 27 revealed a novel binding mode by promoting Cys310-modification.