Pharmacoinformatic Approaches to Design Novel Inhibitors of Protein Kinase B Pathways in Cancer

Abstract

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.

Keywords: Akt inhibitors; PH domain; Protein kinase B; cell apoptosis; rational molecular design; selectivity..