INHIBITON OF AKT TO FIGHT CANCER

by Selleckchem | Aug 06 2012

AKT PATHWAY AND CELL PROLIFERATION
Different types of kinases are involved in the signal transduction pathways. AKT kinase is one such kinase that specifically phosphorylates proteins at their serine/threonine amino acids site. It is also called as PKB i.e., Protein kinase B and is involved multiple types of cellular processes e.g., glucose metabolism, transcription, translation, apoptosis and important of all cell proliferation and its migration. Many of the cancer cells have been found to have AKT dysfunction in them therefore it is considered to have a very important role in cell cycle regulation. AKT gets activated by PI3K and activates itself mTOR protein and further process in the cell gets initiated. Hyperactivation of PI3K increases the rate of cellular process of division etc. and hence takes part in tumorigenesis [1]. This pathway is more frequently found in cancer than any other signal transduction pathway due to the occurrence of mutation, translocation and amplification in its protein kinases [2]. Targeting one of the kinases of this pathway is the strategy to fight against many types of cancers and PKB inhibitors have been found to be quite feasible to be used against cancer.

EFFICIENCY OF AKT INHIBITORS
Research has shown a direct relationship between AKT and cancer, therefore, many different types of inhibitory agents have been discovered and AKT-2 inhibitors are one of such examples. Round about 25 derivatives of isoquinoline and pyridine were made and analyzed against AKT or PKB for its inhibition. The experiments were done in vivo against tumors of mouse xenografts [3]. Elaborate studies of AKT structure has fasten the research for AKT inhibitors [4] in order to use them in pre-clinical and clinical studies. AKT/PI3K pathway was also studied by its allosteric inhibitors and ATP competitors [5]. AKT inhibitors may be bought from the suppliers for any purpose in reasonable prices. Some common types off AKT inhibitors used are A-443654, GSK690693, and Perifosine. Amongst the common inhibitors, MK-2206 has been tested in clinical trials as well. Similar to Aurora A inhibitor, A-443654 also inhibits the expression of Aurora A kinase as well as AKT [6-7] and hence reduces tumor progression. This AKT inhibitor can be used singly or as combinatorial therapy with Rapamycin or Paclitaxel. GSK690693, another AKT inhibitor, has been found to inhibit growth of cancer cells and induce apoptosis in the cell lines of Acute Lymphoblastic leukemia [8].

AKT INHIBITORS IN CLINICS
Different AKT inhibitors have also been brought into clinical trials for example perifosine which is an alkylophospholipid and inhibits PI3K as well as AKT. Keryx Biopharmaceuticals are the manufacturer of the drug hence it has been named KRX-0401. It showed efficacy in clinical trials of phase II in the patients of metastasizing colon cancer, colorectal cancer and in phase III in the patients of MM. for MM and neuroblastoma this drug has been termed as ‘orphan drug’. The drug has also shown promising results in clinical trial phase II in hormone sensitive recurrent patients of prostate cancer [9]. This inhibitor was also checked against relapsed or refractory types of Waldenstrom macroglobulinemia [10]. MK-2206, another AKT inhibitor, showed efficacious results in the patients with advanced solid tumors [11]. AKT inhibitor, VDQ-002, developed by VioQuest biopharmaceutical company, also showed regression in cancer cells in preclinical and clinical trials.

REFERENCES:
1. Hay, N., The Akt-mTOR tango and its relevance to cancer. Cancer Cell, 2005.
2. Hennessy BT, e.a., Exploiting the PI3K/AKT Pathway for Cancer Drug Discovery. Nature Reviews Drug Discovery, 2005.
3. Zhu GD, e.a., Isoquinoline-pyridine-based protein kinase B/Akt antagonists: SAR and in vivo antitumor activity. Bioorganic & Medicinal Chemistry Letters, 2006.
4. Kumar CC, M.V., AKT crystal structure and AKT-specific inhibitors. Oncogene, 2005.
5. Lindsley CW, e.a., The PI3K/Akt Pathway: Recent Progress in the Development of ATP-Competitive and Allosteric Akt Kinase Inhibitors Current Cancer Drug Targets, 2008.
6. Luo Y, e.a., Potent and selective inhibitors of Akt kinases slow the progress of tumors in vivo. Mol Cancer Therap, 2005.
7. Liu X, e.a., Akt Inhibitor A-443654 Interferes with Mitotic Progression by Regulating Aurora A Kinase Expression. Neoplasia, 2008.
8. Levy DS, e.a., AKT inhibitor, GSK690693, induces growth inhibition and apoptosis in acute lymphoblastic leukemia cell lines. Blood, 2011.
9. Chee KG, e.a., The AKT inhibitor perifosine in biochemically recurrent prostate cancer: a phase II California/Pittsburgh cancer consortium trial. Clin Genitourin Cancer., 2007.
10. Ghobrial IM, e.a., Phase II trial of the novel oral Akt inhibitor perifosine in relapsed and/or refractory Waldenstrom macroglobulinemia (WM). J Clin Oncol, 2008.
11. Yap TA, e.a., First-in-Man Clinical Trial of the Oral Pan-AKT Inhibitor MK-2206 in Patients With Advanced Solid Tumors. J Clin Oncol., 2011.

Cat.No.	Product Name	Information
S1078	MK-2206 2HCl	MK-2206 2HCl is a highly selective inhibitor of Akt1/2/3 with IC50 of 8 nM/12 nM/65 nM in cell-free assays, respectively; no inhibitory activities against 250 other protein kinases observed. MK-2206 2HCl induces autophagy and apoptosis in cancer cells. Phase 2.
S1113	GSK690693	GSK690693 is a pan-Akt inhibitor targeting Akt1/2/3 with IC50 of 2 nM/13 nM/9 nM in cell-free assays, also sensitive to the AGC kinase family: PKA, PrkX and PKC isozymes. GSK690693 also potently inhibits AMPK and DAPK3 from the CAMK family with IC50 of 50 nM and 81 nM, respectively. GSK690693 affects Unc-51-like autophagy activating kinase 1 (ULK1) activity, robustly inhibits STING-dependent IRF3 activation. Phase 1.
S1039	Rapamycin	Rapamycin is a specific mTOR inhibitor with IC50 of ~0.1 nM in HEK293 cells.Rapamycin binds to FKBP12 and specifically acts as an allosteric inhibitor of mTORC1. Rapamycin is an autophagy activator and an immunosuppressant.
S1150	Paclitaxel	Paclitaxel is a microtubule polymer stabilizer with IC50 of 0.1 pM in human endothelial cells.Paclitaxel can cause both mitotic arrest and apoptotic cell death. Paclitaxel also induces autophagy.