XAV-939

XAV-939 specifically inhibits tankyrase PARP activity. This compound 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 exposure. Treatment of human lymphoblasts with 1.0 μM this chemical results in marked elevation of tankyrase 1 levels. ^[1]

This agent is axin stabilizing agent. It stimulates beta-catenin degradation by stabilizing axin, the concentration-limiting component of the destruction complex. This compound 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. This chemical deregulates the Wnt/b-catenin pathway which has been implicated in many cancers. ^[2]

XAV-939 (NVP-XAV939) selectively inhibits Wnt/β-catenin-mediated transcription through tankyrase1/2 inhibition.

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 of this compound 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 this chemical 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.

• https://pubmed.ncbi.nlm.nih.gov/21037379/
• https://pubmed.ncbi.nlm.nih.gov/19759537/
• https://pubmed.ncbi.nlm.nih.gov/33128175/