Tankyrase 1/2 Inhibitor VI; G007-LK

Biochem/physiol Actions

Reversible: yes

Cell permeable: yes

Primary TargetTankyrase 1/2

General description

A cell-permeable, triazolyl-vinyl-oxadiazol>e compound that targets adenosine site of the NAD>50> = 33 and 26 nM, respectively, against TNKS1/PARP5a/ARTD5 and TNKS2/PARP5b/ARTD6 in auto-PARsylation assays), effectively inhibiting murine Wnt3a-induced reporter activity in human HEK293 and murine 10T1/2 cultures (IC_>max> ~300 and 600 nM, respectively). Shown to display little or no inhibitory potency (IC_>50> >10 µM) toward 7 other PARP enzymes (PARP1, 2, 3, 6, 7,10,11), 90 kinases, 16 phosphatases, and 75 GPCRs (IC_>50> >10 µM). Shown to inhibit two CRC lines, COLO-320DM & SW403, colony formation >in vitro> (200 nM) and tumor expansion in mice >in vivo> (20 mg/kg via daily i.p.), although G007-LK toxicity is observed at higher dosages (≥30 mg/kg/12 h or 60 mg/kg/d via i.p.).

A cell-permeable, triazolyl-vinyl-oxadiazol>e compound that targets adenosine site of the NAD>50> = 33 and 26 nM, respectively, in TNKS1/PARP5a/ARTD5 and TNKS2/PARP5b/ARTD6 auto-PARsylation assays), effectively inhibiting murine Wnt3a-induced reporter activity in human HEK293 and murine 10T1/2 cultures (IC_>max> ~300 and 600 nM, respectively). In addition to being more selective over PARP1/2 (IC_>50> >10 µM vs 116 nM/47 nM with XAV939) than the nicotinamide site-targeting XAV939 (Cat. No. 30 mg/kg/12 h or 60 mg/kg/d via i.p.) due to small intestine damage as a result of on-target wnt signaling inhibition in normal tissue. Exhibits favorable pharmacokinetic properties in mice when administered via i.p. ( Plasma >t>_>1/2> ≥2.73 h; >C>_>max> ≥2.358 µg/mL; 5 mg/kg) or p.o. ( Plasma >t>_>1/2> ≥2.8 h; >C>_>max> ≥871 ng/mL; 5 mg/kg).

Legal Information

CALBIOCHEM is a registered trademark of Merck KGaA, Darmstadt, Germany

Other Notes

Lau, T., et al. 2013. Cancer Res.73, 3132.Voronkov, A., et al. 2013. J. Med. Chem.56, 3012.

Packaging

Packaged under inert gas

Reconstitution

Following reconstitution, aliquot and freeze (-20°C). Stock solutions are stable for up to 6 months at -20°C.

Warning

Toxicity: Standard Handling (A)