Uses
A-674563 inhibits Akt1, PKA and CDK2 with Ki of 11 nM, 16 nM and 46 nM, respectively.
Biological Activity
a-674563 is a potent and selective akt1 inhibitor with ic50 value of 14 nm. a-67453 also inhibited pka and cdk2 with ic50 value of 16 nm and 46 nm.akt, also known as protein kinase b, is a serine/threonine-specific protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, transcription and cell migration.in miapaca-2 cells treated with a-674563 for 48 hour, it slowed the tumor cell proliferation (ec50 = 0.4 μm). in sts cells, phosphorylation of gsk3 and mdm2 was prominently reduced by a-674563 treatment. [1] akt inhibition-induced g2 cells cycle arrest and apoptosis were also observed in a563-treated sts cells. [2]in scid mice carrying established pc-3 tumors, administration of a-674563 at 40 mg/kg per day for 21 days, combined with administration of paclitaxel at 15 mg/kg per day on days 20.24.28, increased the efficacy of paclitaxel compared with paclitaxel monotherapy. [1] a563 also significantly blocked ht1080 xenograft growth in nude mice. [2]
in vivo
A-674563 (40 mg/kg/d, p.o.) shows no significant monotherapy activity, but the efficacy of the combination therapy (A-674563+paclitaxel) is significantly improved in the PC-3 prostate cancer xenograft model. A-674563 (20, 100 mg/kg) increases plasma insulin in an oral glucose tolerance test[1].
A563 (20 mg/kg/bid; p.o.) exhibits slow tumor growth and a significant difference in tumor volume without significant weight loss of mice. A563-treated tumors express increased levels of GADD45α and decreased levels of PCNA (a nuclear marker for proliferation). Additionally, TUNEL assay staining levels (marker for apoptosis) increase in the A563-treated specimens[2].
A-674563 (25, 100 mg/kg, lavage daily) potently inhibits A375 xenograft growth in mice[3].
A-674563 (15, 40 mg/kg) injection inhibits U937 xenograft in vivo growth, and improves mice survival[4].
IC 50
Akt1: 11 nM (Ki); PKA: 16 nM (Ki); CDK2: 46 nM (Ki); GSK3β: 110 nM (Ki); ERK2: 260 nM (Ki); PKCδ: 360 nM (Ki); RSK2: 580 nM (Ki); MAPK-AP2: 1.1 μM (Ki); PKCγ: 1.2 μM (Ki); Chk1: 2.6 μM (Ki); CK2: 5.4 μM (Ki); SRC: 13 μM (Ki)
References
1. luo y, shoemaker ar, liu x et al. potent and selective inhibitors of akt kinases slow the progress of tumors in vivo. mol cancer ther. 2005 jun;4(6):977-86.2. zhu qs, ren w, korchin b 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 apr 15;68(8):2895-903.
