Navigation Links
Zebrafish swim into drug development
Date:1/21/2010

By combining the tools of medicinal chemistry and zebrafish biology, a team of Vanderbilt investigators has identified compounds that may offer therapeutic leads for bone-related diseases and cancer.

The findings, reported in ACS Chemical Biology, support using zebrafish as a novel platform for drug development.

In 2007, Charles Hong, M.D., Ph.D., and colleagues described using fish embryos to screen for compounds that interfere with signaling pathways involved in early development pathways known to play roles in a variety of disease processes. They discovered the compound "dorsomorphin" and demonstrated that it blocked BMP (bone morphogenetic protein) signaling, which has been implicated in anemia, inflammatory responses and bone-related disorders.

But in examining dorsomorphin further, the investigators found that it had other "off-target" effects it also blocked the VEGF (vascular endothelial growth factor) receptor and disrupted zebrafish blood vessel development, a process called angiogenesis.

"Off-target effects contribute to side effects and limit the therapeutic potential of small molecule signaling inhibitors," said Hong, assistant professor of Medicine and Pharmacology.

To find compounds that were more selective BMP inhibitors (didn't have the off-target effects), Hong and colleagues opted to use their zebrafish drug discovery screen as a drug development/optimization tool.

Craig Lindsley, Ph.D., director of Medicinal Chemistry for the Vanderbilt Program in Drug Discovery, Corey Hopkins, Ph.D., associate director, and their colleagues used the dorsomorphin "backbone" as a starting point to synthesize many different analogs subtly different dorsomorphin-like compounds.

Then Hong and his team tested these compounds for their effects on zebrafish embryonic development.

"We quickly discovered that the two effects of dorsomorphin could be separated some analogs only affected patterning and some only affected angiogenesis," Hong said. The investigators biochemically characterized compounds of both types and found very selective and potent BMP inhibitors and selective VEGF inhibitors.

The zebrafish embryo, Hong said, is very good at assessing a compound's selectivity for a certain signaling pathway. Mixed signals from compounds that are not selective (they hit multiple targets) are toxic to the embryo it "shuts down development."

The team identified a VEGF inhibitor, for example, that outperformed an existing VEGF inhibitor that was being developed for cancer therapy (blocking angiogenesis cuts off the "supply lines" for a growing tumor) but was pulled from development during a Phase III trial.

"If they (the pharmaceutical company) had tested that compound in zebrafish, they would have quickly learned that it wasn't potent or selective," Hong said.

"Using zebrafish is a novel way to do a structure-activity relationship study" a study that examines a series of analog compounds to determine which is the most selective and most potent, he added.

Traditionally, pharmaceutical companies perform these types of studies in vitro, with isolated proteins or cells. But Hong points out that in vitro studies assess only "one dimension" of the biology. Compounds that have great activity in vitro often fail later because they have poor selectivity or because they do not have chemical properties that make them good drugs (they are not "bioavailable").

"The zebrafish assesses selectivity and bioavailability all at the same time," Hong says. "What the traditional approach takes months to do, the zebrafish does in a day."

Because BMP and VEGF inhibitors have therapeutic potential for a variety of diseases, the investigators will begin to test the drug candidates in mouse models.

Hong praised Vanderbilt leaders for putting into place the drug discovery infrastructure that made the work possible.

"Having medicinal chemists and zebrafish biologists together in the same building really fostered our collaboration," he said. "This kind of collaboration would not be likely at the majority of medical institutions."


'/>"/>

Contact: Leigh MacMillan
leigh.macmillan@vanderbilt.edu
615-322-4747
Vanderbilt University Medical Center
Source:Eurekalert

Related biology news :

1. Drug-proof zebrafish reveal secrets of addiction
2. Pitt team finds molecule that regulates heart size by using zebrafish screening model
3. Zebrafish provide a model for cancerous melanoma in humans
4. Alzheimer cell death in Zebrafish: Demise of neurons observed live for the first time
5. AZTI-Tecnalia coordinates a platform promoting the use of zebrafish in scientific research
6. NIH grants Phylonix Phase II SBIR to develop high-throughput in vivo zebrafish assays
7. Digital zebrafish embryo provides the first complete developmental blueprint of a vertebrate
8. Deadly genetic disease prevented before birth in zebrafish
9. A screening strategy using zebrafish targets genes that protect against hearing loss
10. Study shows how the zebrafish gets his stripe
11. Zebrafish to shed light on human mitochondrial diseases
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:4/28/2016)... Sweden , April 28, 2016 First ... M (139.9), up 966% compared with the first quarter of 2015 ... profit totaled SEK 589.1 M (loss: 18.8) and the operating margin ... 7.12 (loss: 0.32) Cash flow from operations was SEK ... The 2016 revenue guidance is unchanged, SEK 7,000-8,500 M. ...
(Date:4/15/2016)... CHICAGO , April 15, 2016  A ... companies make more accurate underwriting decisions in a ... offering timely, competitively priced and high-value life insurance ... health screenings. With Force Diagnostics, rapid ... and lifestyle data readings (blood pressure, weight, pulse, ...
(Date:3/31/2016)... 2016   LegacyXChange, ... "Company") LegacyXChange is excited to release its ... to be launched online site for trading 100% guaranteed ... will also provide potential shareholders a sense of the ... an industry that is notorious for fraud. The video ...
Breaking Biology News(10 mins):
(Date:4/28/2016)... NY (PRWEB) , ... April 28, 2016 , ... ... has made significant investments in recruiting top industry experts, and expanding its LATAM ... which provides industry-leading tools for clients to manage their clinical trial projects. , ...
(Date:4/27/2016)... ... ... Pittcon Organizing Committee is pleased to announce that Charles “Chuck” Gardner was named president ... Since then, he has served in a number of key leadership positions including secretary ... and exposition committees. In his professional career, Dr. Gardner is the director of product ...
(Date:4/27/2016)... British Virgin Islands (PRWEB) , ... April 27, ... ... Holding Company Ltd. (d/b/a Biohaven) is pleased to announce the appointment of John Tilton ... he was an Executive Director and one of the founding commercial leaders responsible ...
(Date:4/27/2016)... ... 27, 2016 , ... Global Stem Cells Group CEO Benito Novas ... founder of GSCG affiliate Kimera Labs in Miami. , In 2004, Ross received his ... transplantation for hematologic disorders and the suppression of graft vs. host disease (GVHD) under ...
Breaking Biology Technology: