Background:
Protein kinase B (PKB/Akt) belongs to the AGC superfamily of related serine/
threonine kinases with three structurally homologous mammalian isoforms, Akt1 (PKBα), Akt2
(PKBβ), and Akt3 (PKBγ). Besides sharing a similar structural topology, the difference in their
physiological functions and tissue distribution makes Akt a cardinal node in diverse signaling pathways
involving cell growth, survival, and proliferation. Various immunohistochemical studies have
reported that the constitutive hyperactivation of Akt signaling is responsible for several types of human
cancer, poor prognosis, as well as chemotherapeutic and radiotherapeutic resistance. Thus, inhibition
of Akt activation represents a promising concept to induce cell apoptosis in various cancers
and evade chemotherapeutic resistance. However, development of potent and selective inhibitors of
Akt kinases as suitable antagonists remained gloomy and thus, only handful of compounds were selected
for the clinical investigation but none of them could reach the market for routine clinical usage
to circumvent cell proliferation and resistance to chemotherapeutic agents in cancer. Recent reports
on achieving isoform selectivity by designing inhibitors against PH domain of Akt, together
with availability of crystal structures of the PH domain of Akt1, open the possibility of structurebased
design.
Methods:
In this article, various biological regulatory networks by which Akt and its substrates
regulate cell growth and survival and several SAR and QSAR strategies in combination with molecular
docking studies on selective inhibitors of Akt subtypes have been highlighted to further
probe the selectivity of ligand-Akt subtypes interactions.
Results:
Structure-based drug design studies revealed that the interactions of structurally diverse
compounds with Glu121, Ala123, Asn171, Asp184, Glu228 and Ala230 amino acid residues in CAT
domain and Arg23, Arg25, Lys30, Asn54 and Arg86 amino acid residues within PH domain play an
important role in attaining significant inhibitory potency.
Conclusion:
Isoform selective inhibition of Akt might have clinical significance and thus, should be
taken into account in future investigations. Moreover, an up to date isoform selective chemical data
is required to further validate already reported isoform selective binding hypothesis.
Activation of the essential kinase PDK1 by phosphoinositide-driven autophosphorylation
