Porcn Inhibitor IV, LGK974

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.

Cell permeable: yes

Primary Target
Porcupine

Reversible: yes

Packaged under inert gas

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

Liu, J., et al. 2013. Proc. Natl. Acad. Sci. USA110, 20224.

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

Toxicity: Standard Handling (A)