Biological Activity
Vevorisertib (ARQ 751) trihydrochloride is a selective, allosteric, pan-AKT and AKT1-E17K mutant inhibitors. Vevorisertib trihydrochloride potently inhibit phosphorylation of AKT. Vevorisertib trihydrochloride has Kd values of 1.2 nM and 8.6 nM for AKT1 and AKT1-E17K, respectively. Vevorisertib trihydrochloride has IC50 values of 0.55, 0.81, and 1.3 nM for AKT1, AKT2, and AKT3, respectively. Vevorisertib trihydrochloride can be used for the research of cancer[1].
Vevorisertib trihydrochloride (0, 12, 33, 111, 333, 1000 nM, 2 hours) inhibits phosphorylation of AKT1-E17K[1].Vevorisertib trihydrochloride (1 μM for 2 hours; NIH 3T3 cells are transfected with either pcDNAAKT-WT-GFP or pcDNA-E17K-GFP) inhibits plasma membrane translocation of AKT-WT and AKT1-E17K irrespective of the presence of growth factors[1].Vevorisertib trihydrochloride (5 μM) exhibites 57% inhibition of full-length AKT1[1].Vevorisertib trihydrochloride (0, 0.012, 0.037, 0.11, 0.33, 1 μM; 2 hours) shows a dose-dependent effect on mTORC1 and AKT direct substrates including PRAS40, GSK3β, FOXO, BAD, and AS160 in cancer cell lines[1].Vevorisertib trihydrochloride has anti-proliferative effect on esophageal, breast, and head and neck cancer cells (GI50 < 1 μM)[1].Vevorisertib trihydrochloride exhibits strong anti-proliferative activity in PIK3CA mutant cell lines[1].Vevorisertib trihydrochloride (MK-4440)/imatinib mesylate (IM) combination shows cell cycle arrest, and increases cell death of gastrointestinal stromal tumor (GIST) cells[2].Vevorisertib trihydrochloride exhibits strong anti-proliferative activity in PIK3CA mutant cell lines[1]: Breast Cancer Cell Lines GI50 (nM) PIK3CA ER PR HER2 T47D 1.05 H1047R + + - EFM-19 1.54 H1047R + + - MCF-7 2.20 E545K + + - BT474 3.25 K111N + + + MDA-MB-453 6.05 H1047R - - +
Vevorisertib trihydrochloride (25, 50 and 75 mg/kg; p.o.; 5 days dosing followed by a 4 day dosing holiday for 20 days) shows potent tumor growth inhibition of 68, 78 and 98%, respectively[1].Vevorisertib trihydrochloride (5, 10, 20, 40, 80, and 120 mg/kg; p.o. daily for ten days) shows tumor growth inhibition of 29, 33, 50, 73, 83, and 92%, respectively[1].Vevorisertib trihydrochloride reachs Cmax plasma concentrations of ≥2 μM[1].Vevorisertib trihydrochloride is generally well-tolerated at dose levels up to 120 mg/kg[1].Vevorisertib trihydrochloride (MK-4440)/IM combination shows superior efficacy in an IM-sensitive preclinical model of GIST compared with either single agent[2].
References
[1]. Yu Y, et al. Targeting AKT1-E17K and the PI3K/AKT Pathway with an Allosteric AKT Inhibitor, ARQ 092. PLoS One. 2015 Oct 15;10(10):e0140479. [2]. Kozinova M, et al. Combined Inhibition of AKT and KIT Restores Expression of Programmed Cell Death 4 (PDCD4) in Gastrointestinal Stromal Tumor. Cancers (Basel). 2021 Jul 23;13(15):3699.
