MK-2206 (free base)

MK-2206 free base is an orally active pan-AKT inhibitor, with IC₅₀ values of 8 nM, 12 nM and 65 nM against AKT1, AKT2 and AKT3, respectively. MK-2206 free base inhibits the Akt/mTOR signaling pathway and reduces the levels of downstream GSK3β and Mcl-1 via proteasomal degradation. MK-2206 free base induces G1-phase cell cycle arrest, apoptosis (apoptosis), epithelial-mesenchymal transition, fibroblast activation and extracellular matrix deposition. MK-2206 free base causes transient hyperglycemia and hyperinsulinemia in animals. MK-2206 free base can be used in research related to solid tumors, renal fibrosis and hypercholesterolemia^[1][2][3][4]. IC50 & Target:8, 12, and 65 nM (Akt1, Akt2, and Akt3)^[1] In Vitro:MK-2206 free base inhibits Akt1 kinase activity in various human cancer cell lines with an IC₅₀ of approximately 20 nM, blocks the downstream signaling pathway of Akt, and exerts potent antiproliferative effects on cancer cell lines with specific PI3K pathway gene defects, while activation of the Ras pathway predicts no response^[1].
MK-2206 free base exerts additive or synergistic antiproliferative and pro-apoptotic sensitizing effects when combined with various chemotherapeutic agents and targeted inhibitors in relevant human cancer cell lines^[1].
MK-2206 (72 h) free base potently inhibits the growth of U937, OCI/AML3, MV-4-11 and MOLM-13 acute myeloid leukemia (AML) cell lines, with IC₅₀ values ranging from 0.6 to 2.5 μM, while it exhibits only extremely low cytotoxicity against normal human peripheral blood mononuclear cells (PBMCs)^[2].
MK-2206 (1-10 μM; 24 h) free base induces dose-dependent G₁ cell cycle arrest in OCI/AML3, MOLM-13 and MV-4-11 AML cell lines^[2].
MK-2206 (1-10 μM; 24 h) free base induces dose-dependent apoptosis in OCI/AML3, MOLM-13 and MV-4-11 acute myeloid leukemia (AML) cell lines, with a significant increase in apoptotic cell populations at higher doses^[2].
MK-2206 (0.1-10 μM; 2-24 h) free base induces apoptosis in MV-4-11 acute myeloid leukemia (AML) cells via caspase-3 and PARP cleavage, downregulates Mcl-1 protein levels in MV-4-11, OCI/AML3 and U937 AML cells in a dose-dependent manner, and inhibits the phosphorylation of Akt at Ser⁴⁷³ and GSK3β at Ser⁹ after 2 to 24 h of treatment, respectively^[2].
MK-2206 (10 μM; 1-4 h) free base induces downregulation of Mcl-1 in MV-4-11 acute myeloid leukemia (AML) cells via a GSK3β-mediated proteasome-dependent mechanism^[2].
Combined administration of MK-2206 (200 nM; 72 h) free base and Cytarabine (HY-13605) synergistically enhances cytotoxicity in MV-4-11, MOLM-13 and OCI/AML3 acute myeloid leukemia (AML) cell lines (ED₅₀ CI value < 1), but exhibits antagonistic effects in U937 AML cells (ED₅₀ CI value = 1.13)^[2].
MK-2206 (0.5-5 μM; 48 h) free base inhibits TGF-β1-induced fibrosis, epithelial-mesenchymal transition (EMT), and activation of the Akt/mTOR signaling pathway in HK-2 cells. The effective concentration is 1 μM, which reduces the mRNA expression of Collagen I and Fibronectin, restores E-cadherin levels, and suppresses the expression of mesenchymal markers and phosphorylated Akt/mTOR proteins^[3].
MK-2206 (0.5-20 μM; 2-24 h) free base upregulates LDLR protein levels in HepG2 cells treated with sterol feeding or sterol starvation. The maximum induction effect is observed in the sterol starvation group treated with 5 μM for 14 h, while that in the sterol feeding group is achieved with 10 μM treatment for 14 h. Moreover, a significant induction effect occurs within 4 h of treatment with 5 μM^[4].
MK-2206 (2.5-5 μM; 2-6 h) free base inhibits the activity of AKT kinase in sterol-fed HepG2 cells. At concentrations ≥2.5 μM, it reduces the phosphorylation levels of AKT and its downstream target PRAS40 within 2 h^[4].
MK-2206 (5 μM; 14 h) free base increases cell-surface LDLR expression and stimulates LDL uptake in HepG2 cells under both sterol-fed and sterol-starved conditions^[4].
MK-2206 (5-12 μM; 2-24 h) free base induces LDLR mRNA expression in sterol-fed HepG2 cells within 2 h through a mechanism that enhances transcription (rather than mRNA stabilization) and is independent of de novo protein synthesis^[4].
MK-2206 (5-10 μM; 14 h) free base upregulates LDLR protein levels in sterol-fed IHH, HeLa, IMH, and Hepac1c7 cells^[4].
MK-2206 (5 μM; 24 h) free base inhibits de novo cholesterol biosynthesis in HepG2 cells under sterol starvation conditions^[4].
MK-2206 (5 μM; 14 h) free base upregulates LDLR protein levels in CHO cells and HMGCR-deficient UT-2 cells, indicating that this effect is independent of HMGCR activity^[4].
MK-2206 (0.5-4 μM; 38 h) free base enhances the LDLR (low-density lipoprotein receptor)-inducing effect of Mevastatin (HY-17408) in sterol-starved HepG2 cells^[4].
MK-2206 (5 μM; 2-24 h) free base upregulates the mRNA expression of PCSK9, HMGCR, SREBP-2 and HMGCS1 in sterol-fed HepG2 cells, exerts only minor effects on ACACA, FASN and SCD1, and has no effect on IDOL^[4].
MK-2206 (2.5-5 μM; 14-24 h) free base stimulates LDLR promoter activity in sterol-fed HepG2 cells in an SRE-1-dependent manner^[4].
MK-2206 (5 μM; 14-24 h) free base upregulates LDLR mRNA levels in sterol-fed HepG2 cells in an SREBP-2-dependent manner^[4].
MK-2206 (5 μM; 2-6 h) free base stimulates proteolytic cleavage of FL-SREBP-2 to generate the active NTF-SREBP-2 in sterol-fed HepG2 cells^[4].
MK-2206 (2.5-10 μM; 14 h) free base upregulates LDLR protein levels in primary adult hepatocytes^[4]. In Vivo:MK-2206 free base enhances the anti-tumor efficacy of multiple chemotherapeutic agents in preclinical ovarian cancer xenograft models and induces mild, transient hyperglycemia and hyperinsulinemia in animals that resolves post-treatment^[1].
MK-2206 (120 mg/kg; p.o.; alternate days; 4 total doses) free base alleviates UUO-induced renal fibrosis in mice by reducing inflammation, inhibiting epithelial-mesenchymal transition, suppressing myofibroblast activation and extracellular matrix deposition, and blocking activation of the Akt/mTOR signaling pathway^[3].