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: Protein kinase B, PH domain, Akt inhibitors, selectivity, cell apoptosis, rational molecular design.
Graphical Abstract
Current Cancer Drug Targets
Title:Pharmacoinformatic Approaches to Design Novel Inhibitors of Protein Kinase B Pathways in Cancer
Volume: 18 Issue: 9
Author(s): Noreen Akhtar and Ishrat Jabeen*
Affiliation:
- Research Center for Modeling and Simulation (RCMS), National University of Sciences and Technology (NUST), Sector H-12, 44000, Islamabad,Pakistan
Keywords: Protein kinase B, PH domain, Akt inhibitors, selectivity, cell apoptosis, rational molecular design.
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.
Export Options
About this article
Cite this article as:
Akhtar Noreen and Jabeen Ishrat*, Pharmacoinformatic Approaches to Design Novel Inhibitors of Protein Kinase B Pathways in Cancer, Current Cancer Drug Targets 2018; 18 (9) . https://dx.doi.org/10.2174/1568009617666170623104540
DOI https://dx.doi.org/10.2174/1568009617666170623104540 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
Related Books

- Author Guidelines
- Bentham Author Support Services (BASS)
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
Related Articles
-
Estrogen Receptors as Targets for Drug Development for Breast Cancer, Osteoporosis and Cardiovascular Diseases
Current Cancer Drug Targets Intravitreal Injections and Diabetic Macular Edema: Actual and New Therapeutic Options
Current Diabetes Reviews The Zinc Metallopeptidase Family: New Faces, New Functions
Protein & Peptide Letters Vasoproliferation and Antiproliferative Treatment Options in Pulmonary Arterial Hypertension
Recent Patents on Cardiovascular Drug Discovery Epigallocatechin-3-Gallate Prevents Autoimmune-Associated Down- Regulation of p21 in Salivary Gland Cells Through a p53-Independent Pathway
Inflammation & Allergy - Drug Targets (Discontinued) Bisphosphonate Therapy for Patients with Breast Cancer
Current Cancer Therapy Reviews Peptides for Diagnosis and Treatment of Colorectal Cancer
Current Medicinal Chemistry Base-Modified Nucleosides as Chemotherapeutic Agents: Past and Future
Current Topics in Medicinal Chemistry A Review of the Chemical and Pharmacological Aspects of the Genus Marrubium
Current Pharmaceutical Design iPSCs Derived from Malignant Tumor Cells: Potential Application for Cancer Research
Current Stem Cell Research & Therapy In vitro Evaluation of Gadolinium-Silica Mesoporous Nanoparticles- Monoclonal Antibody: Potential Nanoprobe for Prostate Cancer Cell Imaging
Current Molecular Imaging (Discontinued) HIV-1 Infection: Recent Developments in Treatment and Current Management Strategies
Anti-Infective Agents in Medicinal Chemistry Stress Induction of GRP78/BiP and Its Role in Cancer
Current Molecular Medicine Revolutionary Impact of Nanodrug Delivery on Neuroscience
Current Neuropharmacology Muscarinic Activation Enhances the Anti-proliferative Effect of Paclitaxel in Murine Breast Tumor Cells
Anti-Cancer Agents in Medicinal Chemistry Nanoscale Functional Biomaterials for Cancer Theranostics
Current Medicinal Chemistry Natural Polymeric Nanoparticles for Brain-Targeting: Implications on Drug and Gene Delivery
Current Pharmaceutical Design A Role for TGF-β Signaling in Neurodegeneration: Evidence from Genetically Engineered Models
Current Alzheimer Research Optimization of the Enzymolysis Conditions for Scorpion Peptides and Evaluation of its Antitumor Activity
Current Signal Transduction Therapy Let-7a Could Serve as A Biomarker for Chemo-Responsiveness to Docetaxel in Gastric Cancer
Anti-Cancer Agents in Medicinal Chemistry