Pharmacological evaluation of a series of smoothened antagonists in signaling pathways and after topical application in a depilated mouse model

Abstract

The Hedgehog (HH) pathway has been linked to the formation of basal cell carcinoma (BCC), medulloblastoma, and other cancers. The recently approved orally active drugs vismodegib (GDC‐0449) and sonidegib (LDE–225) were not only efficacious for the treatment of advanced or metastatic BCC by antagonizing the smoothened (SMO) receptor, but also produced important side effects, limiting their use for less invasive BCC. Herein, we compared a large series of SMO antagonists, including GDC‐0449 and LDE‐225, the clinically tested BMS‐833923, CUR‐61414, cyclopamine, IPI‐926 (saridegib), itraconazole, LEQ‐506, LY‐2940680 (taladegib), PF‐04449913 (glasdegib), and TAK‐441 as well as preclinical candidates (PF‐5274857, MRT‐83) in two SMO‐dependent cellular assays and for G‐protein activation. We report marked differences in inhibitor potencies between compounds as well as a notable disparity between the G‐protein assay and the cellular tests, suggesting that classification of drugs is assay dependent. Furthermore, we explored topical efficacies of SMO antagonists on depilated mice using Gli1 and Ptch1 mRNA quantification in skin as biomarkers of the HH signaling inhibition. This topical model rapidly discriminated drugs in terms of efficacies and potencies for inhibition of both biomarkers. SMO antagonists showed also a large variation in their blood and skin partition, suggesting that some drugs are more favorable for topical application. Overall, our data suggested that in vitro and in vivo efficacious drugs such as LEQ‐506 and TAK‐441 may be of interest for topical treatment of less invasive BCC with minimal side effects.

The role of the Hedgehog signaling pathway in cancer: A comprehensive review

“…Hh ligand inhibitors act at the highest level of the signaling pathway by inhibiting the binding of Hh protein to Ptch receptor [145]. On the other hand, Smo antagonists bind to the Smo drug-binding pocket, thus preventing the downstream activation of the Hh signaling cascade [146]. Smo inhibitors currently used in clinical trials are IPI-926 (saridegib), BMS833923 (XL-139), PF04449913 (glasdegib), LY2940680 (taladegib), LEQ506, and TAK-441, whereas GDC-0449 (vismodegib) and LDE225 (sonidegib) have been approved by the US Food and Drug Administration, but are not in use yet [22,147,148].…”

Sonidegib: mechanism of action, pharmacology, and clinical utility for advanced basal cell carcinomas

“…For example, LEQ-506 and TAK-441 are favorable in the treatment of minimally invasive BCC due to their properties in a topical formulation and their low side effects. In contrast, sonidegib and vismodegib have stronger side effects, limiting their use in less invasive BCCs 57. The development of these SMO inhibitors promises the coming of therapies that will offer diverse properties in terms of treatment indications, clinical efficacy, and safety profiles 58–60…”

Topical itraconazole formulations: Unscrupulous pharmaceutical companies and lax indian drug regulators endangering a precious drug

“…Interestingly, we were unable to find any published paper in an indexed journal on the use of topical itraconazole in dermatophyte infections of the skin. The only published clinical studies of topical itraconazole use on the skin refer to its activity as a hedgehog signaling pathway inhibitor in the treatment/prophylaxis of basal cell carcinoma in mice[ 24 ] and humans. [ 25 ] Even in these studies, it failed to reach high enough concentrations in the epidermal tumors to have a clinical effect on human skin.…”