MK-2206, as a pan Akt inhibitor

by Selleckchem | Oct 09 2012

MK-2206
AKT/Protein Kinase B is a serine/threonine-specific protein kinase that constitutes an important pathway that regulates the signaling of multiple essential biological processes such as glucose metabolism, apoptosis, cell proliferation, and cell migration. AKT can be recruited to the membrane and activated with increases in PIP3 induced by PI3K. Since activating mutations of PI3K occur in human tumors, the AKT pathway is a promising potential target for cancer chemotherapy. [1] MK-2206, is identified as an orally bioavailable allosteric inhibitor of Akt with potential antineoplastic activity. MK-2206 has shown cytotoxic activity in vitro cell line, such as T-cell acute lymphoblastic leukemia (T-ALL)[2], and the efficacy of MK-2206 also has been proven in preclinical models of human cancers.

ACTION MECHANISM OF MK-2206

As an Akt inhibitor, MK-2206 inhibits the activity of Akt in a non-ATP competitive manner, and further results in the inhibition of the PI3K/Akt signaling pathway and cell proliferation and the induction of cell apoptosis. Scientists and researchers have studied the action mechanism of MK-2206. As is known, Akt possesses a protein domain called Pleckstrin Homology (PH) domain, which binds with high affinity to phosphoinositides including PIP3 and PIP2. As reported about the mechanism of action previously, allosteric Akt inhibitors not only block Akt kinase activity but also inhibit Akt activation by blocking phosphorylation of Akt on T308 and S473. Though the mechanism of action of MK-2206 is not entirely understood, existing data suggest that binding of inhibitor induces a closed conformation that occludes binding sites for activating kinases PDK1 and mTORC2, and Akt substrates, and further disrupts membrane localization. [3]

CLINICAL TRIALS
MK-2206, as a member from this class of Akt inhibitors, has recently entered clinical development. The safety and tolerability, pharmacokinetics, pharmacodynamics and anti-tumor activity of MK-2206 has been evaluated in Phase 1 in Locally Advanced or Metastatic Solid Tumors, including Ovarian Cancer, Fallopian Tube Cancer, and Primary Peritoneal Cancer. In addition, Phase 2 Study of MK-2206 in Patients With Relapsed Refractory Acute Myelogenous Leukemia is currently recruiting participants. Besides, combination study of Everolimus and other drugs is in process. Of which, the Phase I Study of MK-2206 in combination with standard doses of chemotherapies or targeted agents, such as carboplatin, paclitaxel, docetaxel and erlotinib, has been completed in patients with Locally Advanced or Metastatic Solid Tumors. We will continue to follow up on the new clinical studies about MK-2206 and the related combination therapy.

REFERENCES
[1] Carnero A. The PKB/AKT pathway in cancer. Curr Pharm Des. 2010, 16(1), 34-44.
[2] Simioni C, et al. Cytotoxic activity of the novel Akt inhibitor, MK-2206, in T-cell acute lymphoblastic leukemia. Leukemia. 2012, doi:10.1038/leu.2012.136.
[3] Cherrin C, et al. An allosteric Akt inhibitor effectively blocks Akt signaling and tumor growth with only transient effects on glucose and insulin levels in vivo. Cancer Biol Ther. 2010, 9(7), 493-503.

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.
S1215	Carboplatin	Carboplatin, a derivative of CDDP, is a DNA synthesis inhibitor which binds to DNA, inhibits replication and transcription and induces cell death and interfers with the cell's repair mechanism in A2780, SKOV-3, IGROV-1, and HX62 cells. It induces the formation of DNA interstrand crosslinks and DNA-protein crosslinks. Solutions are unstable and should be fresh-prepared.DMSO is not recommended to dissolve platinum-based drugs, which can easily lead to drug inactivation.
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.
S1148	Docetaxel	Docetaxel, an analog of paclitaxel, is an inhibitor of depolymerisation of microtubules by binding to stabilized microtubules.
S1023	Erlotinib HCl	Erlotinib HCl is an EGFR inhibitor with IC50 of 2 nM in cell-free assays, >1000-fold more sensitive for EGFR than human c-Src or v-Abl.