Structure–Activity Relationships and Mechanism of Action of Small Molecule Smoothened Modulators Discovered by High-Throughput Screening and Rational Design

  • Fabrizio ManettiEmail author
  • Maurizio Taddei
  • Elena Petricci
Part of the Topics in Medicinal Chemistry book series (TMC, volume 16)


Smoothened (Smo) is the signal transducer of the Hedgehog (Hh) pathway and its stimulation or inhibition is considered a potential powerful tool in regenerative medicine and for the treatment of cancer. In the last years, many natural and nonnatural small molecules have been identified that are able to modulate the Hh pathway. Most of them target Smo, while only a few compounds are able to interact directly with upstream and downstream Hh pathway components. Although several compounds showed a remarkable potency and selectivity, their use induced emergence of mutated and resistant cell lines. In an attempt to find new chemical entries able to affect the Hh pathway and overcome limitation imposed by mutations and resistance, academic researchers and pharmaceutical companies are making further efforts to identify new drug-like small molecules to be included in the currently available therapeutic protocols for several types of cancers or in regenerative medicine and tissue repair.


Hedgehog signaling Hit-to-lead compound optimization Small molecule Smoothened antagonists and agonists Structure–activity relationships Synthesis 



Alcohol dehydrogenase 7


Absorption, distribution, metabolism, excretion, toxicity


Alkaline phosphatase


Acute promyelocytic leukemia


Basal cell carcinoma


Boron dimethylpyrrolydene


Chronic myelogenous leukemia


Cysteine-rich domain


Cytochrome P24A1


Cytochrome P450


Desert Hedgehog


Diversity-oriented synthesis


Half-maximal effective concentration


Food and Drug Administration


Fluorescence resonance energy transfer


Glioma-associated oncogene homologue (Gli) antagonist


Granular cell precursor


Green fluorescent protein


50% inhibition of cell growth


Glioma-associated oncogene homologue 1–3

Gli-Luc assay

Glioma-associated oncogene homologue-luciferase assay


G protein-coupled receptor




Human embryonic palatal mesenchymal cells


Human ether-à-go-go-related gene




Hedgehog agonist


Hedgehog antagonist 691


Hedgehog pathway inhibitors


High-throughput screening


Half-maximal inhibitory concentration


Indian Hedgehog




Lithium bis(trimethylsilyl)azanide


Mitogen-activated protein kinase


Methyl iodide






Piperonyl butoxide


Protein kinase C


Prostate specific antigen




Pregnane X receptor


Retinoic acid, epidermal growth factor, nerve growth factor induced gene protein


Smoothened agonist


Smoothened antagonist


Structure–activity relationships


Supercritical fluid chromatography


Sonic Hedgehog


N-terminal tail of sonic Hedgehog


Smoothened mutant antagonist




Oncogenic Smoothened (Smo) mutant


Suppressor of fused


Transmembrane helix


Vitamin D2


Vitamin D3


Vitamin D receptor






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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Fabrizio Manetti
    • 1
    Email author
  • Maurizio Taddei
    • 1
  • Elena Petricci
    • 1
  1. 1.Department of Biotechnology, Chemistry and PharmacyUniversity of SienaSienaItaly

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