P62 Pre-Clinical Pharmacological and Skin Penetration Profile of LDE255, a Novel and Specific Smoothened Antagonist

LDE225, a novel and selective Smoothened (Smo) antagonist with a molecular weight of 485, demonstrated high affinity for human and mouse Smo, surpassing cyclopamine by over 20-fold. The study showed that LDE225 effectively inhibited the formation and induced regression of basaloid tumors in Ptch1± heterozygous knock-out mice with an IC50 of less than 150 nmol/l, and almost complete regression at 1.5 μmol/l. Additionally, topical application of LDE225 at 1% concentration completely inhibited hair growth and Hedgehog-pathway target gene expression in C57/BL6 mice during the anagen phase of hair growth. LDE225 penetrated well into human and pig skin in vitro, with low permeation through the skin, and in vivo application to pigs resulted in dermal concentrations of 1–1.5 μg/g and minimal blood levels. These results suggest that LDE225 has potential as a topical treatment for basal cell carcinoma due to its favorable skin penetration and pharmacological properties.