scholarly journals Small-Molecule Screening in Zebrafish Embryos Identifies Signaling Pathways Regulating Early Thyroid Development

Thyroid ◽  
2019 ◽  
Vol 29 (11) ◽  
pp. 1683-1703 ◽  
Author(s):  
Benoit Haerlingen ◽  
Robert Opitz ◽  
Isabelle Vandernoot ◽  
Achim Trubiroha ◽  
Pierre Gillotay ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Small Molecule ◽  
Zebrafish Embryos ◽  
Small Molecule Screening ◽  
Thyroid Development

scholarly journals Small Molecule Screening in Zebrafish Embryos Identifies Signaling Pathways Regulating Early Thyroid Development

2019 ◽  
Author(s):  
Benoit Haerlingen ◽  
Robert Opitz ◽  
Isabelle Vandernoot ◽  
Achim Trubiroha ◽  
Pierre Gillotay ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Small Molecule ◽  
Molecular Mechanisms ◽  
Model Organisms ◽  
Thyroid Cell ◽  
Zebrafish Embryos ◽  
Cardiovascular Development ◽  
Drug Induced ◽  
Thyroid Development

AbstractBackgroundDefects in embryonic development of the thyroid gland are a major cause for congenital hypothyroidism in human newborns but the underlying molecular mechanisms are still poorly understood. Organ development relies on a tightly regulated interplay between extrinsic signaling cues and cell intrinsic factors. At present, however, there is limited knowledge about the specific extrinsic signaling cues that regulate foregut endoderm patterning, thyroid cell specification and subsequent morphogenetic processes in thyroid development.MethodsTo begin to address this problem in a systematic way, we used zebrafish embryos to perform a series of in vivo phenotype-driven chemical genetic screens to identify signaling cues regulating early thyroid development. For this purpose, we treated zebrafish embryos during different developmental periods with a panel of small molecule compounds known to manipulate the activity of major signaling pathways and scored phenotypic deviations in thyroid, endoderm and cardiovascular development using whole mount in situ hybridization and transgenic fluorescent reporter models.ResultsSystematic assessment of drugged embryos recovered a range of thyroid phenotypes including expansion, reduction or lack of the early thyroid anlage, defective thyroid budding as well as hypoplastic, enlarged or overtly disorganized presentation of the thyroid primordium after budding. Our pharmacological screening identified BMP and FGF signaling as key factors for thyroid specification and early thyroid organogenesis, highlight the importance of low Wnt activities during early development for thyroid specification and implicate drug-induced cardiac and vascular anomalies as likely indirect mechanisms causing various forms of thyroid dysgenesis.ConclusionsBy integrating the outcome of our screening efforts with previously available information from other model organisms including Xenopus, chicken and mouse, we conclude that signaling cues regulating thyroid development appear broadly conserved across vertebrates. We therefore expect that observations made in zebrafish can inform mammalian models of thyroid organogenesis to further our understanding of the molecular mechanisms of congenital thyroid diseases.

scholarly journals Use of Zebrafish Embryos for Small Molecule Screening Related to Cancer

2013 ◽  
Vol 242 (2) ◽  
pp. 97-107 ◽  
Author(s):  
Javier Terriente ◽  
Cristina Pujades
Keyword(s):  
Small Molecule ◽  
Zebrafish Embryos ◽  
Small Molecule Screening

scholarly journals Identification of a Novel Retinoid by Small Molecule Screening with Zebrafish Embryos

PLoS ONE ◽  
2008 ◽  
Vol 3 (4) ◽  
pp. e1947 ◽  
Author(s):  
Chetana Sachidanandan ◽  
Jing-Ruey J. Yeh ◽  
Quinn P. Peterson ◽  
Randall T. Peterson
Keyword(s):  
Small Molecule ◽  
Zebrafish Embryos ◽  
Small Molecule Screening

Synthesis of Elaborate Benzofuran-2-Carboxamide Derivatives Through a Combination of 8-Aminoquinoline Directed C–H Arylations and Transamidations

2019 ◽  
Author(s):  
Michael Oschmann ◽  
Linus Johansson Holm ◽  
Oscar Verho
Keyword(s):  
Small Molecule ◽  
High Efficiency ◽  
Synthetic Strategy ◽  
Small Molecule Screening ◽  
Physiological Properties ◽  
Wide Range ◽  
Directing Group ◽  
Synthetic Sequence

Benzofurans are everywhere in nature and they have been extensively studied by medicinal chemists over the years because of their chemotherapeutic and physiological properties. Herein, we describe a strategy that can be used to access elaborate benzo-2-carboxamide derivatives, which involves a synthetic sequence of 8-aminoquinoline directed C–H arylations followed by transamidations. For the directed C–H arylations, Pd catalysis was used to install a wide range of aryl and heteroaryl substituents at the C3 position of the benzofuran scaffold in high efficiency. Directing group cleavage and further diversification of the C3-arylated benzofuran products were then achieved in a single synthetic operation through the utilization of a two-step transamidation protocol. By bocylating the 8-aminoquinoline amide moiety of these products, it proved possible to activate them towards aminolysis with different amine nucleophiles. Interestingly, this aminolysis reaction was found to proceed efficiently without the need of any additional catalyst or additive. Given the high efficiency and modularity of this synthetic strategy, it constitute a very attractive approach for generating structurally-diverse collections of benzofuran derivatives for small molecule screening.

Towards drugging the ‘undruggable’: enhancing the scaffold diversity of synthetic small molecule screening collections using diversity-oriented synthesis

2013 ◽  
Vol 1 (1) ◽  
Author(s):  
Warren R.J.D. Galloway ◽  
David R. Spring
Keyword(s):  
Small Molecule ◽  
Structural Diversity ◽  
Library Size ◽  
Diversity Oriented Synthesis ◽  
Biological Targets ◽  
Small Molecule Screening ◽  
Chemistry Research ◽  
Large Numbers ◽  
Small Molecule Libraries ◽  
Scaffold Diversity

AbstractMedicinal chemistry research has traditionally focused upon a limited set of biological targets. Many other human disease-related targets have been termed ‘undruggable’ as they have proved largely impervious to modulation by small molecules. However, it is becoming increasingly evident that such targets can indeed be modulated; they are simply being challenged with the wrong types of molecules. Traditionally, screening libraries were composed of large numbers of structurally similar compounds. However, library size is not everything; the structural diversity of the library, which is largely dictated by the range of molecular scaffolds present, is crucial. Diversity-oriented synthesis (DOS) generates small molecule libraries with high levels of scaffold, and thus structural, diversity. Such collections should provide hits against a broad range of targets with high frequency, including ‘undruggable’ targets. Examples in the area of scaffold diversity generation taken from the author’s laboratories are given.

P031 The last 10%: small molecule screening for correctors of rare CFTRprocessing mutations

2021 ◽  
Vol 20 ◽  
pp. S48
Author(s):  
M. Ensinck ◽  
L. De Keersmaecker ◽  
M. Nijs ◽  
A.S. Ramalho ◽  
K. De Boeck ◽  
...  
Keyword(s):  
Small Molecule ◽  
Small Molecule Screening
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