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

Abstract

The Hedgehog (Hh) pathway is critical for cell differentiation, tissue polarity, and stem cell maintenance during embryonic development, but is silent in adult tissues under normal conditions. However, aberrant Hh signaling activation has been implicated in the development and promotion of certain types of cancer, including basal cell carcinoma (BCC), medulloblastoma, and gastrointestinal cancers. In 2015, the US Food and Drug Administration (FDA) approved sonidegib, a smoothened (SMO) antagonist, for treatment of advanced BCC (aBCC) after a successful Phase II clinical trial. Sonidegib, also named Odomzo, is the second Hh signaling inhibitor approved by the FDA to treat BCCs following approval of the first SMO antagonist vismodegib in 2012. What are the major features of sonidegib (mechanism of action; metabolic profiles, clinical efficacy, safety, and tolerability profiles)? Will the sonidegib experience help other clinical trials using Hh signaling inhibitors in the future? In this review, we will summarize current understanding of BCCs and Hh signaling. We will focus on sonidegib and its use in the clinic, and we will discuss ways to improve its clinical application in cancer therapeutics.

Keywords: Hedgehog; basal cell carcinoma; cancer; inhibitor; smoothened; sonidegib.

Figure 1

Canonical Hh signaling and noncanonical Hh signaling. Abbreviations: Hh, Hedgehog; PTCH, patched; Shh, Sonic hedgehog; SMO, smoothened.

Figure 2

Generation of Sonidegib. Notes: (A) The structure of compound #1 from a cell-based screening. (B) The structure of sonidegib, which has high biological potency.

Figure 3

Sonidegib interacts with the drug-binding pocket of SMO, which mainly consists of three amino acids: arginine (R) 473, arginine (R) 400, and glutamic acid (E) 518. Abbreviation: SMO, smoothened.