A Zebrafish-Based Platform for Nuclear Receptor Drug Screening and Pathway Discovery in Metabolic Disease and Cancer


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Challenge: Nuclear receptors (NRs) are a family of proteins that regulate gene expression in many vital processes such as metabolism, growth and behaviour. They are also implicated in a large array of diseases such as diabetes, Parkinson’s, Alzheimer’s and cancer. Consequently, nuclear receptors represent one of the most important class of targets for existing drugs. However, mainly due to a lack of appropriate screening platforms, there has been a massive decline in recent NR-directed drug discovery.

Solution: The team has developed a novel, in vivo, high throughput drug screening platform to visualize and isolate human nuclear receptor (NR) ligands in transgenic zebrafish. Zebrafish embryos were used as they are transparent, develop ex utero, can be obtained in large numbers, and are amenable to high throughput pharmacological screens. The platform is based on (i) zebrafish lines expressing a sensitive green fluorescent protein (GFP) reporter that reveals the ligand’s location and activity in the animal, and allows automated screening for changes in fluorescent activity, and (ii) ligand-trapping that allows for purification and identification of activated NRs and small molecule ligands from tissues. A subset of the transgenic zebrafish lines was used to identify new hormones, drugs, genetic pathways and disease indications.

Achievements/Impact: The team established 32 transgenic NR zebrafish lines for the screening and identification of nuclear receptor-targeted drugs against metabolic diseases and cancer. The platform was validated by screening compound libraries and identifying ten new ligands for five human nuclear receptor lines. The platform also allowed the identification of endogenous ligands for three orphan nuclear receptors, including one for the PPAR nuclear receptors alpha and gamma. A synthetic analog of this ligand, idebenone, was also identified as a partial agonist and its effect confirmed in mice. This platform was instrumental in the development of InDanio, a service-oriented CRO offering high-throughput in vivo screening of new chemical entities targeting the nuclear receptor protein family.

Principal Investigators:
Henry Krause
University of Toronto/
InDanio Biosciences
Vincent Giguère
McGill University
Jens Tiefenbach
InDanio Bioscience
Completed Project
$ 549,000 / 3 years
Supported by CQDM through:
– Merck
– Pfizer
And by a co-funding partner:
– Ontario Centres of Excellence
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