INHIBITON OF AKT FOR THE TREATMENT OF CANCER

by Selleckchem | Aug 10 2012

CELL PROLIFERATION AND AKT PATHWAY
Signal transduction pathways involve various types of kinase enzymes. AKT kinase is such an enzyme that is responsible of phosphorylating the proteins on their specifically serine/threonine sites specifically. It is also named as PKB which means Protein kinase B. It is involved in different kinds of cellular processes like apoptosis, transcription, translation, metabolism and the most important of above all is the cell proliferation and cell migration. Many cancerous cells have been found to exhibit AKT dysfunction therefore it is thought to have an important role in the regulation of cell cycle. AKT pathway gets active by stimulation from PI3K and it also activates by itself mTOR protein to initiate the further process. When PI3K gets hyperactivated, there is an increase in rate of cell division process etc. hence caused tumorigenesis [1]. As compared to any other pathway of signal transduction, this AKT pathway exists more frequently in the cancer cells due to event of amplification, mutation and translocation in its kinase proteins [2]. To fight against various types of cancers and tumors the strategy applied is to target any one of these kinase proteins of this pathway and the AKT inhibitors were found quite good to be used for the treatment of cancer.

AKT PROTEIN INHIBITORS: EFFICIENT ONES
Research on AKT has revealed that this pathway has a very direct relationship with cancer, hence various different types of inhibiting agents have been designed and the AKT-3 inhibitors are amongst the examples of such inhibitors. Around 25 pyridine and isoquinoline derivatives were designed and analyzed to inhibit PKB and AKT pathway. In vivo experiments were performed against the xenografts of mouse tumors [3]. Detailed study of structure of AKT has more fasten the critical study for AKT protein inhibitors [4] to use them in clinical and pre-clinical studies. AKT/PI3K pathway was also analyzed by using its ATP competitors and allosteric inhibitors [5]. These inhibitors can be bought from respective suppliers in reasonable prices for any purposes. Some of these commonly used types of AKT inhibitors are GSK690693, Perifosine and A-443654. Amongst these common inhibitors the type MK-2206 has been studied in clinical studies as well. A-443654, like Aurora C inhibitor has also found to inhibit the Aurora A kinase expression as well as PKB or AKT [6-7] hence is reducing the tumor progression. Specifically this AKT inhibitor may be used singly or in a combination with Paclitaxel or Rapamycin. Another AKT or PKB inhibitor named GSK690693, has been observed to inhibit the growth of cancerous cells hence inducing the apoptosis process in the cell lines of ALL or Acute Lymphoblastic leukemia [8].

AKT INHIBITORS: IN CLINICS
Various AKT inhibitors have been brought to clinical trials, for instance perifosine that is an alkylophospholipid in nature and inhibits AKT and PI3K as well. The drug has been manufactured by Keryx Biopharmaceuticals and has been named as KRX-0401. It was proved very efficient in its phase II clinical trials against the patients of colorectal cancer, metastasizing colon cancer and clinical trials phase of III against the patients of MM. hence for neuroblastoma and MM, this chemical agent has been named as ‘orphan drug’. This drug has also revealed some promising results in clinical studies of phase II against the hormone sensitive patients of recurrent prostate cancer [9]. This drug was also tested for treating the refractory or relapsed types of Waldenstrom macroglobulinemia [10]. Another AKT inhibitor is VDQ-002 that is designed by a famous biopharmaceutical company; VioQuest has also shown regression in the cancer cells during their clinical and preclinical 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
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.
S1037	Perifosine	Perifosine is a novel Akt inhibitor with IC50 of 4.7 μM in MM.1S cells, targets pleckstrin homology domain of Akt. Phase 3.
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.
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.