A-674563 is an orally active and selective Akt1 inhibitor with a Ki of 11 nM.
IC50&Target
Akt1
11 nM (Ki)
PKA
16 nM (Ki)
PKCγ
1.2 μM (Ki)
PKCδ
360 nM (Ki)
SRC
13 μM (Ki)
CDK2
46 nM (Ki)
ERK2
260 nM (Ki)
GSK3β
110 nM (Ki)
CK2
5.4 μM (Ki)
Chk1
2.6 μM (Ki)
RSK2
580 nM (Ki)
MAPK-AP2
1.1 μM (Ki)
体外研究
A-674563 slows proliferation of tumor cells with an EC50 of 0.4 μM.
A563 (0-10 µM) significantly decreases GSK3 and MDM2 phosphorylation in STS cells. A563 shows inhibitory effect on all STS cell lines, with IC50 values at 48 hours ranging from 0.22 µM (SW684) to 0.35 µM (SKLMS1). A563 induces G2 cell cycle arrest and apoptosis in STS cells. A563 (1 µM/12 hr) upregulates the expression of GADD45A independent of p53.
A-674563 (10-1000 nM) is anti-proliferative and cytotoxic in cultured human melanoma cells, induces melanoma cell apoptotic death, inhibited by caspase inhibitors, and inhibits melanoma cells via Akt-dependent and -independent mechanisms.
A-674563 is cytotoxic and anti-proliferative when added to U937 and AmL progenitor cells, activates caspase-3/9 and apoptosis in U937 and AmL progenitor cells, and manipulates other signalings in AmL cells whiling blocking Akt.
体内研究
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.
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.
A-674563 (25, 100 mg/kg, lavage daily) potently inhibits A375 xenograft growth in mice.
A-674563 (15, 40 mg/kg) injection inhibits U937 xenograft in vivo growth, and improves mice survival.
分子式
C22H22N4O
分子量
358.44
CAS号
552325-73-2
运输条件
Room temperature in continental US; may vary elsewhere.