Abstract
Invasion and metastasis are responsible for 90% of cancer-related mortality. Herein, we report on our quest for novel, clinically relevant inhibitors of local invasion, based on a broad screen of natural products in a phenotypic assay. Starting from micromolar chalcone hits, a predictive QSAR model for diaryl propenones was developed, and synthetic analogues with a 100-fold increase in potency were obtained. Two nanomolar hits underwent efficacy validation and eADMET profiling; one compound was shown to increase the survival time in an artificial metastasis model in nude mice. Although the molecular mechanism(s) by which these substances mediate efficacy remain(s) unrevealed, we were able to eliminate the major targets commonly associated with antineoplastic chalcones.
Keywords:
Cancer; Chalcone; Invasion; In vivo; Metastasis; QSAR.
Copyright © 2015 Elsevier Masson SAS. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
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Validation Study
MeSH terms
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Animals
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Antineoplastic Agents, Phytogenic / chemical synthesis
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Antineoplastic Agents, Phytogenic / chemistry
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Antineoplastic Agents, Phytogenic / pharmacology*
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Antineoplastic Agents, Phytogenic / therapeutic use
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Biological Products / chemical synthesis
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Biological Products / chemistry
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Biological Products / pharmacology*
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Biological Products / therapeutic use
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Cell Line, Tumor
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Cell Movement / drug effects
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Cell Survival / drug effects
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Chalcones / chemical synthesis
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Chalcones / chemistry
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Chalcones / pharmacology*
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Chalcones / therapeutic use*
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Chick Embryo
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Drug Discovery*
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Female
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Humans
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Mice
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Mice, Nude
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Molecular Structure
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Myocardium / pathology
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Neoplasm Invasiveness / pathology
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Neoplasm Invasiveness / prevention & control*
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Neoplasm Metastasis / drug therapy*
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Neoplasm Metastasis / pathology
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Quantitative Structure-Activity Relationship
Substances
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4-fluoro-3',4',5'-trimethoxychalcone
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Antineoplastic Agents, Phytogenic
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Biological Products
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Chalcones