State of the art of Smo antagonists for cancer therapy: advances in the target receptor and new ligand structures

Since the Hedgehog signaling pathway has been associated with cancer, it has emerged as a therapeutic target for cancer therapy. The main target among the key Hedgehog proteins is the GPCR-like Smo receptor. Therefore, some Smo antagonists that have entered clinical trials, including the US FDA-appr...

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Bibliographic Details
Published in:Future medicinal chemistry 2019-03, Vol.11 (6), p.617-638
Main Authors: Espinosa-Bustos, Christian, Mella, Jaime, Soto-Delgado, Jorge, Salas, Cristian O
Format: Article
Language:English
Subjects:
Animals
anticancer compounds
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Basal cell carcinoma
Cancer
Cancer therapies
cancer therapy
Cell adhesion & migration
Cell growth
Clinical trials
Drug Design
Drug development
Drug resistance
G protein-coupled receptors
Hedgehog protein
Hedgehog Proteins - antagonists & inhibitors
Hedgehog Proteins - metabolism
Hedgehog signaling pathway
Humans
Ligands
Medulloblastoma
Metastasis
Models, Molecular
Molecular Targeted Therapy - methods
Mutation
Neoplasms - drug therapy
Neoplasms - metabolism
Pathogenesis
Protein Conformation - drug effects
Proteins
Signal transduction
Signal Transduction - drug effects
Skin cancer
Smo antagonists
Smoothened receptor
Smoothened Receptor - antagonists & inhibitors
Smoothened Receptor - chemistry
Smoothened Receptor - metabolism
Stem cells
Therapeutic applications
Transcription factors
Tumorigenesis
Tumors
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Summary:Since the Hedgehog signaling pathway has been associated with cancer, it has emerged as a therapeutic target for cancer therapy. The main target among the key Hedgehog proteins is the GPCR-like Smo receptor. Therefore, some Smo antagonists that have entered clinical trials, including the US FDA-approved drugs vismodegib and sonidegib, to treat basal cell carcinoma and medulloblastoma. However, early resistance of these drugs has spawned the need to understand the molecular bases of this phenomena. We therefore reviewed details about Smo receptor structures and the best Smo antagonist chemical structures. In addition, we discussed strategies that should be considered to develop new, safer generations of Smo antagonists that avoid current clinical limitations.
ISSN:1756-8919
1756-8927
DOI:10.4155/fmc-2018-0497