A-674563 hydrochloride

• CAT Number: I005867
• Molecular Formula: C22H23ClN4O
• Molecular Weight: 394.9
• Purity: ≥95%
• Target: Akt1
• Solubility: DMSO: ≥ 30mg/mL
• Storage: Store at -20°C
• IC50: 14nm

A-674563 hydrochloride 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. 


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. 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. 


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. 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.  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.

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Reference

[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.