Abstract
Hedgehog (Hh) inhibitors have emerged as valid tools in the treatment of a wide range of cancers. Indeed, aberrant activation of the Hh pathway occurring either by ligand-dependent or -independent mechanisms is a key driver in tumorigenesis. The smoothened (Smo) receptor is one of the main upstream transducers of the Hh signaling and is a validated target for the development of anticancer compounds, as underlined by the FDA-approved Smo antagonist Vismodegib (GDC-0449/Erivedge) for the treatment of basal cell carcinoma. However, Smo mutations that confer constitutive activity and drug resistance have emerged during treatment with Vismodegib. For this reason, the development of new effective Hh inhibitors represents a major challenge for cancer therapy. Natural products have always represented a unique source of lead structures in drug discovery, and in recent years have been used to modulate the Hh pathway at multiple levels. Here, starting from an in house library of natural compounds and their derivatives, we discovered novel chemotypes of Hh inhibitors by mean of virtual screening against the crystallographic structure of Smo. Hh functional based assay identified the chalcone derivative 12 as the most effective Hh inhibitor within the test set. The chalcone 12 binds the Smo receptor and promotes the displacement of Bodipy-Cyclopamine in both Smo WT and drug-resistant Smo mutant. Our molecule stands as a promising Smo antagonist able to specifically impair the growth of Hh-dependent tumor cells in vitro and in vivo and medulloblastoma stem-like cells and potentially overcome the associated drug resistance.
Highlights
Hedgehog (Hh) signaling is a morphogenetic pathway that has a crucial role during embryonic development and tissues homeostasis.[1,2,3] In vertebrates, Hh pathway activation is mediated by two transmembrane receptors: Patched[1] (Ptch1), endowed with inhibitory functions, and Smoothened (Smo), which is the central transducer of Hh pathway and belongs to the class F (Frizzled) G protein-coupled receptor family
To identify natural products chemotypes of Smo antagonists, an in house library of natural and synthetic compounds was screened in silico against the crystallographic structure of Smo bound to Cyclopamine (PDB: 4O9R).[28]
The potential Smo antagonists 1–17 identified in silico show a noticeable range of chemical diversity and differ for their source, which is either natural or synthetic
Summary
Hedgehog (Hh) signaling is a morphogenetic pathway that has a crucial role during embryonic development and tissues homeostasis.[1,2,3] In vertebrates, Hh pathway activation is mediated by two transmembrane receptors: Patched[1] (Ptch1), endowed with inhibitory functions, and Smoothened (Smo), which is the central transducer of Hh pathway and belongs to the class F (Frizzled) G protein-coupled receptor family.
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