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:12/15/2016)... ... has announced the addition of the "Global Military Biometrics Market 2016-2020" ... global military biometrics market to grow at a CAGR of 7.5% during ... on an in-depth market analysis with inputs from industry experts. The report ... The report also includes a discussion of the key vendors operating in ...
(Date:12/15/2016)... , Dec. 14, 2016 "Increase in ... biometrics market" The mobile biometrics market is expected to ... 49.33 billion by 2022, at a CAGR of 29.3% ... factors such as the growing demand for smart devices, ... transactions. "Software component is expected to grow ...
(Date:12/8/2016)... 8, 2016  Singulex, Inc., the leader in Next ... into a license and supply agreement with Thermo Fisher ... provides Singulex access to Thermo Scientific BRAHMS PCT (Procalcitonin), ... is used to diagnose systemic bacterial infection and sepsis ... to aid in assessing the risk of critically ill ...
Breaking Biology News(10 mins):
(Date:1/18/2017)... ... January 18, 2017 , ... ... funded bio-focused Manufacturing Innovation Institutes (MII). U.S. Secretary of Commerce Penny Pritzker has ... (NIIMBL), and the Department of Defense has announced the award of a new ...
(Date:1/18/2017)... PA (PRWEB) , ... January 18, 2017 , ... ... operations again at the CHI SCOPE Summit for Clinical Ops Executives (Hyatt Regency ... engaging panel discussions to examine vital clinical research issues such as trial performance ...
(Date:1/18/2017)... ... January 18, 2017 , ... Thirty-six startup companies in University ... the Pennsylvania Department of Community and Economic Development in 2016 as part of the ... the University City Keystone Innovation Zone and represent the highest number of awards to ...
(Date:1/18/2017)...  Caris Life Sciences, a leading innovator in ... private funder of pancreatic cancer research, are collaborating ... of immunotherapy in the treatment of pancreatic cancer. ... identify potential trial candidates based on biomarker expression ... study investigators. The Lustgarten Foundation is a sponsor ...
Breaking Biology Technology: