A-674563 (hydrochloride)

中文名称:

A-674563 (hydrochloride)

中文同义词:

AKT1抑制剂(A-674563 HYDROCHLORIDE)

英文名称:

A-674563 (hydrochloride)

英文同义词:

A-674563 (hydrochloride);A-674563 hydrochloride (A 674563 hydrochloride

CAS号:

2070009-66-2

分子式:

C??H??ClN?O

分子量:

0

EINECS号:

相关类别:

细胞生物学试剂

Mol文件:

Mol File

生物活性

A-674563 hydrochloride 是具有选择性的高效 Akt1 抑制剂，其 Ki 值为 11 nM。

靶点

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)

Akt1 11 nM (Ki)

PKA 16 nM (Ki)

体外研究

A-674563 slows proliferation of tumor cells with an EC 50 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 IC 50 values at 48 hours ranging from 0.22±0.034 µM (SW684) to 0.35 ±0.06 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.