Protein kinase B (PKB or Akt) is a central component of the PI3K – PKB –
mTOR signaling 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.
Keywords: Protein kinase B, AKT, inhibitors, cancer, mTOR, ATP competitive
inhibitor, PKB inhibitor, allosteric modulation, substrate peptide mimetic
inhibitors.
