Protein kinase B (PKB or Akt) is a central component of the PI3K - PKB - mTOR signalling cascade and is firmly established as an attractive target for pharmacological intervention in cancer. A number of small molecule inhibitors with well-defined, direct molecular interactions with PKB are now known, covering a range of mechanisms from ATP- or substrate-competitive inhibition, through allosteric modulation of the kinase activity, to inhibition of the phosphatidylinositol-dependent activation process. The development of small molecule inhibitors of PKB has benefited greatly from the application of structural biology techniques, particularly for lead generation and the optimisation of compound potency and selectivity. The development of the major chemical series of PKB inhibitors will be outlined, with an emphasis on the application of structure-based design and the strategies used to optimise compound pharmacodynamics, efficacy and therapeutic window. The development of small molecules targeting PKB for anticancer therapy has reached an exciting stage, with the first selective inhibitors entering clinical trials, and several additional chemotypes demonstrating efficacy in preclinical models.
