AKT INHIBITORS AS ANTI TUMOR AGENTS

by Selleckchem | Jul 24 2012

AKT PATHWAY AND CANCERS:
AKT is a kinase specific for threonine/serine amino acids which is also known as Protein kinase kinase B (PKB). This kinase is involved in various cellular pathways such as glucose metabolism, apoptosis, transcription and the most important functions are cell migration and proliferation. In cancer cells many of the crucial functions are controlled by AKT which depicts its importance. AKT is downstream to PI3K and mostly it is hyper activated during formations of cancers therefore taking a part in tumorigenesis through a hyperactive PI3K/AKT/mTOR pathway [1]. As mutations, translocations and amplifications in PI3K/AKT/mTOR pathway result into hyperactivation of this pathway are more frequent than other signaling pathways [2]. AKT inhibitors are one of the most feasible approaches to fight against cancer.

EFFECT OF AKT INHIBITORS ON AKT PATHWAY:
There is a link between AKT signaling and formation of tumors as reported by researchers and AKT-1 inhibitors are developed to control cancer growth. Pyridine and isoquinoline based more than 25 derivatives were designed by a research group and these were analyzed as PKB or AKT antagonists. These experiments were based on mouse xenografts models for in vivo actions against tumors [3]. AKT structure elucidation speeded up the specific inhibitors of AKT pathway [4] which are ultimately to be used in clinical and preclinical studies. The pathway of AKT/PI3K was checked by ATP competitor and allosteric inhibitors [5]. These AKT inhibitors are available in reasonable prices and one can buy these for laboratory uses from any of the suppliers. Some of the famous AKT inhibitors are GSK690693, A-443654 and Perifosine and amongst these MK-2206 is being evaluated in clinical trials. Like Aurora kinase inhibitors, A-443654 inhibits Aurora A kinase expression along with AKT pathway [6-7] which reduces the tumor progression and this agent can be used in a single for or in combination with other potential anti-cancer agents like Paclitaxel or Rapamycin. On the other hand GSK690693 reported to inhibit cancer cell growth and induces apoptosis in ALL cell lines lymphoblastic leukemia [8].

CLINICAL TRIALS OF AKT INHIBITORS:
Perifosine is one of the examples of AKT inhibitors in clinical trials which is a alkylophospholipid and it also inhibits PI3K inhibitor. This is also known as KRX-0401 as this drug was manufactured by Keryx Biopharmaceuticals, Perifosine generated efficient results during clinical phase II trials in which patients of metastatic colon cancer and colorectal cancer and MM in phase III trials. This is also having a status as ‘orphan drug’ for neuroblastoma and MM. In hormone sensitive patients recurrent of prostate cancers Perifosine also inhibited AKT phosphorylation in 2nd phase of clinical trials [9]. Refractory or relapsed forms of Waldenstrom macroglobulinemia was also checked by this inhibitor [10]. MK-2206 also showed efficient results in clinical trials having patients with solid advanced tumors [11]. VDQ-002 is another AKT inhibitor which is involved in the regression of cancers during clinical trials and preclinical success this inhibitor was developed by VioQuest pharmaceutical company.

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.
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.
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.