TANKYRASE 1/2 INHIBITOR VI 1 PC X 10 MG

General description

A cell-permeable, triazolyl-vinyl-oxadiazole compound that targets adenosine site of the NAD⁺ pocket in the TNKS PARP domain and acts as a potent and highly selective tankyrase inhibitor (IC₅₀ = 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 (IC₅₀ >10 µM) toward 7 other PARP enzymes (PARP1, 2, 3, 6, 7,10,11), 90 kinases, 16 phosphatases, and 75 GPCRs (IC₅₀ >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.).

Please note that the molecular weight for this compound is batch-specific due to variable water content.

A cell-permeable, triazolyl-vinyl-oxadiazole compound that targets adenosine site of the NAD⁺ pocket in the TNKS PARP domain and acts as a potent and highly selective tankyrase inhibitor (IC₅₀ = 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 (IC₅₀ >10 µM vs 116 nM/47 nM with XAV939) than the nicotinamide site-targeting XAV939 (Cat. No. 575545), G007-LK is also shown to display little or no inhibitory potency (IC₅₀ >10 µM) toward 5 other PARP enzymes (PARP3, 6, 7,10,11), 90 kinases, 16 phosphatases, and 75 GPCRs (IC₅₀ >10 µM). Wnt signaling inhibition upon G007-LK treatment in 11 APC (Adenomatous polyposis coli/deleted in polyposis 2.5/DP2.5) mutatant CRC (colorectal cancer) lines ranges from no effect to varying degrees of partial blockages that do not correlate with the observed CRC colony formation inhibitions.Two CRC lines, COLO-320DM & SW403, whose colony formation are affected by G007-LK in vitro (by 70% and 27%, respectively, at 200 nM in 7 to 13 d) are also inhibited by G007-LK for their tumor expansion in mice in vivo (by 47% and 42%, respectively, on d21; 20 mg/kg per daily i.p.), while G007-LK toxicity is observed at high dosages in mice (≥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).

Biochem/physiol Actions

Cell permeable: yes

Primary Target
Tankyrase 1/2

Reversible: yes

Packaging

Packaged under inert gas

Warning

Toxicity: Standard Handling (A)

Reconstitution

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

Other Notes

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

Legal Information

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