Brief Description

A-674563 is a potent selective Akt1 inhibitor with an IC50 of 14 nM; also shows inhibitory activity against PKA and CDK2 with IC50 of 16 and 46 nM, respectively.
IC50 value: 14 nM (Akt1)
Target: Akt1; PKA
in vitro: A-674563 is achieved from A-443654 by replacing the indole with a phenyl moiety and getting oral activity. A-674563 slows proliferation of tumor cells with EC50 of 0.4 μM [1]. A-674563 does not inhibit Akt phosphorylation per se, but blocks the phosphorylation of Akt downstream targets in a dose-dependent manner. A-674563 induced Akt blockade results in decreased STS cell downstream target phosphorylation and tumor cell growth inhibiton. A-674563 induces G2 cell cycle arrest and apoptosis in STS cells [2].
in vivo: 20 mg/kg A-674563 increases plasma insulin in an oral glucose tolerance test. A-674563 shows no significant monotherapy tumor inhibitory activity; the efficacy of the combination therapy is significantly improved compared to paclitaxel monotherapy [1]. A674563-treated (20 mg/kg/bid, p.o.) mice exhibits slower tumor growth and more than 50% decrease in the tumor volume at the termination of the study compared with that in control group. [2] A-674563 is identified to have drastically improved PK profile with oral bioavailability of 67% in mouse, but is 70-fold less active than A-443654 [3].
References on A-674563:
[1]. Luo Y, et al. Potent and selective inhibitors of Akt kinases slow the progress of tumors in vivo. Mol Cancer Ther, 2005, 4(6), 977-986.
[2]. Zhu QS, et al. Soft tissue sarcoma cells are highly sensitive to AKT blockade: a role for p53-independent up-regulation of GADD45 alpha. Cancer Res, 2008, 68(8), 2895-2903.
[3]. Tatsuya Okuzumi, et al. Synthesis and evaluation of indazole based analog sensitive Akt inhibitors. Mol Biosyst, 2010, 6(8), 1389-1402.

Solubility

DMSO ≥70mg/mL; Water ≥70mg/mL; Ethanol ≥10mg/mL

Melting point

Boiling point

Density

Formula Weight:

Flash point

Storage conditions

Store at -20°C 2 years

Appearance:

White to off-white solid