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The Smoothened Receptor in Cancer and Regenerative Medicine pp 43–107Cite as

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

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Part of the book series: Topics in Medicinal Chemistry ((TMC,volume 16))

Abstract

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.

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Abbreviations

Adh7:

Alcohol dehydrogenase 7

ADMETox:

Absorption, distribution, metabolism, excretion, toxicity

AP:

Alkaline phosphatase

APL:

Acute promyelocytic leukemia

BCC:

Basal cell carcinoma

BODIPY:

Boron dimethylpyrrolydene

CML:

Chronic myelogenous leukemia

CRD:

Cysteine-rich domain

Cyp24A1:

Cytochrome P24A1

Cyp450:

Cytochrome P450

Dhh:

Desert Hedgehog

DOS:

Diversity-oriented synthesis

EC50 :

Half-maximal effective concentration

FDA:

Food and Drug Administration

FRET:

Fluorescence resonance energy transfer

GANT:

Glioma-associated oncogene homologue (Gli) antagonist

GCP:

Granular cell precursor

GFP:

Green fluorescent protein

GI50 :

50% inhibition of cell growth

Gli1-3:

Glioma-associated oncogene homologue 1–3

Gli-Luc assay:

Glioma-associated oncogene homologue-luciferase assay

GPCR:

G protein-coupled receptor

h:

Hour

HEPM:

Human embryonic palatal mesenchymal cells

hERG:

Human ether-à-go-go-related gene

Hh:

Hedgehog

Hh-Ag:

Hedgehog agonist

Hh-Antag691:

Hedgehog antagonist 691

HPI:

Hedgehog pathway inhibitors

HTS:

High-throughput screening

IC50 :

Half-maximal inhibitory concentration

Ihh:

Indian Hedgehog

KAAD-cyclopamine:

3-keto-N-(aminoethyl-aminocaproyl-dihydrocinnamoyl)cyclopamine

LiHMDS:

Lithium bis(trimethylsilyl)azanide

MAPK:

Mitogen-activated protein kinase

MeI:

Methyl iodide

mL:

Milliliter

nM:

Nanomolar

PBO:

Piperonyl butoxide

PKC:

Protein kinase C

PSA:

Prostate specific antigen

Ptch:

Patched

PXR:

Pregnane X receptor

Ren:

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

SAG:

Smoothened agonist

SANT:

Smoothened antagonist

SAR:

Structure–activity relationships

SFC:

Supercritical fluid chromatography

Shh:

Sonic Hedgehog

ShhN:

N-terminal tail of sonic Hedgehog

SMANT:

Smoothened mutant antagonist

Smo:

Smoothened

SmoM2:

Oncogenic Smoothened (Smo) mutant

SuFu:

Suppressor of fused

TM:

Transmembrane helix

VD2:

Vitamin D2

VD3:

Vitamin D3

VDR:

Vitamin D receptor

μg:

Microgram

μM:

Micromolar

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  1. Department of Biotechnology, Chemistry and Pharmacy, University of Siena, via A. Moro 2, 53100, Siena, Italy

    Fabrizio Manetti, Maurizio Taddei & Elena Petricci

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    Martial Ruat

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Manetti, F., Taddei, M., Petricci, E. (2014). Structure–Activity Relationships and Mechanism of Action of Small Molecule Smoothened Modulators Discovered by High-Throughput Screening and Rational Design. In: Ruat, M. (eds) The Smoothened Receptor in Cancer and Regenerative Medicine. Topics in Medicinal Chemistry, vol 16. Springer, Cham. https://doi.org/10.1007/7355_2014_61

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