化合物信息

Description

Cancer

Description

XAV-939 is a selective Wnt β-catenin-mediated transcription inhibitor for TNKS1 and TNKS2 with IC50 of 11 nM and 4 nM, respectively.

Targets

IC₅₀

In Vitro

XAV-939 specifically inhibits tankyrase PARP activity. XAV-939 dramatically decreases DNA-PKcs protein levels, confirming the critical role of tankyrase poly-ADP-ribosylation activity in maintaining stability of the DNA-PKcs protein. The greatest reduction of DNA-PKcs protein levels (< 25%="" relative="" expression="" compared="" to="" dmso="" treated="" controls)="" occurs="" at="" 12="" hours="" with="" 1.0="" μm="" xav-939="" exposure.="" treatment="" of="" human="" lymphoblasts="" with="" 1.0="" μm="" xav-939="" results="" in="" marked="" elevation="" of="" tankyrase="" 1="" levels.="">^[1] XAV-939 is axin stabilizing agent. XAV-939 stimulates beta-catenin degradation by stabilizing axin, the concentration-limiting component of the destruction complex. XAV-939 stabilizes axin by blocking the poly-ADP-ribosylating enzymes tankyrase 1 and tankyrase 2. Both tankyrase isoforms interact with a highly conserved domain of axin and stimulate its degradation through the ubiquitin-proteasome pathway. XAV-939 deregulates the Wnt/b-catenin pathway which has been implicated in many cancers. ^[2]

In Vivo

Clinical Trials

Features

Cell Lines

WTK1 lymphoblasts

Concentrations

1.0 μM

Incubation Time

8 hours

Methods

XAV-939 is solubilized in DMSO at 55 °C to make a 10 mM stock solution which may be diluted later to a working concentration of 100 μM. WTK1 lymphoblasts treated with either DMSO or 1.0 μM XAV-939 for 8 hours are loaded into independent wells of a 4-20% gradient SDS-PAGE every 2 hours over the course of 6 hours. At each time point, DMSO and XAV-939 samples are loaded into wells immediately adjacent to the prior time point. The corresponding load times at 0, 2 and 4 hours results in total run times of 2, 4 and 6 hours respectively. The gel is analyzed via western blot for DNA-PKcs following completion of the final run time and is quantified after normalization to actin loading controls.