General description
A cell-permeable C59 (Cat. No. 500496) structural analog that potently inhibits TM3 cellular Wnt pathway activation-dependent transcription by blocking Wnt secretion from co-cultured L-cells (IC50 from 50 pM to 1.1 nM using Wnt1/2/3/3a/6/7a/9a L-cell transfectants) via direct porcupine (Porcn), but not Wntless, affinity interaction. Shown to inhibit Wnt-dependent proliferation of head and neck squamous cell carcinoma (HNSCC) line HN30 (IC50 = 0.3 nM in 48 h colony formation assay), but not the growth of 293T even at concentrations as high as 20 µM. In mice & rats receiving therapeutic LGK974 oral dosages (up to 5 mg/10 mL/kg/d), a delayed tissue Wnt signaling suppression (max inhibition 7 to 10 h post dosing) is seen due to pre-existing Wnt in tissue, followed by a full recovery of tissue Wnt signalling at 24 h upon drug clearance. The periodic daily inhibition/recovering cycle is shown to result in tumor regression in mice & rats harboring tumors derived from human HNSCC HN30 or tumor fragments from murine mammary tumor virus (MMTV)-Wnt1 transgenic mice, while allowing Wnt signaling-dependent normal tissue homeostasis. Overdosing is reported to result in loss of intestinal epithelium in rats receiving 14 consecutive 20 mg/kg daily oral dosages.
A cell-permeable C59 (Cat. No. 500496) structural analog that potently inhibits Wnt secretion from L-cell Wnt1/2/3/3a/6/7a/9a transfectants (IC50 from 50 pM to 1.1 nM) via direct porcupine (Porcn), but not Wntless, affinity interaction. Shown to inhibit the proliferation of head and neck squamous cell carcinoma (HNSCC) line HN30 (IC50 = 0.3 nM), but not 293T even at a high concentration of 20 µM. In mice & rats receiving therapeutic LGK974 oral dosages (up to 5 mg/10 mL/kg/d), a delayed tissue Wnt signaling suppression (max inhibition 7 to 10 h post dosing) is seen due to pre-existing Wnt in tissue, followed by a full recovery of tissue Wnt signalling at 24 h upon drug clearance. The periodic daily inhibition/recovering cycle is shown to result in tumor regression in mice & rats, while allowing Wnt signaling-dependent normal tissue homeostasis. Overdosing is reported to result in loss of intestinal epithelium in rats receiving 14 consecutive 20 mg/kg daily oral dosages.
Biochem/physiol Actions
Cell permeable: yes
Primary Target
Porcupine
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
Liu, J., et al. 2013. Proc. Natl. Acad. Sci. USA110, 20224.
Legal Information
CALBIOCHEM is a registered trademark of Merck KGaA, Darmstadt, Germany
- UPC:
- 12352200
- Condition:
- New
- Weight:
- 1.00 Ounces
- HazmatClass:
- No
- WeightUOM:
- LB
- MPN:
- 5310910001