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Dart Hires Galapagos’ BioFocus to Develop CBAs, Run HTP Screens for Brain Disorders

Galapagos’ service division, BioFocus DPI, and Dart Neuroscience this week announced two new collaboration agreements in drug discovery and compound management that could be worth up to €4.1 million ($5.5 million) over three years for Galapagos.
Terms of the first deal call for BioFocus DPI to develop cell-based assays for Dart's drug-discovery program for brain disorders, and perform high-throughput screening and hit expansion using compound collections acquired from commercial vendors, a Dart official told CBA News this week.
The deal also calls for BioFocus DPI to perform compound management for DNS over the next three years.
The second portion of the agreement, which will also run for three years, calls for BioFocus to acquire 200,000 undisclosed commercially available compounds for Dart, Tim Tully, Dart’s chief scientific officer, explained. These compounds will be acquired from undisclosed vendors within seven months from the signing of the agreement.
The first part of the deal “represents the first step that Dart Neuroscience is taking to assemble its own in-house compound library and begin screening novel targets,” Tully said.
He cited BioFocus’s track record with the National Institutes of Health as Dart’s reason to hire it as a contract research organization to screen one of its more than 1,000 proprietary gene targets, and to acquire and manage the initial stages of Dart’s own drug library. 
Terms of the agreement call for BioFocus to develop cell-based assays to perform high-throughput screens for an undisclosed gene target held by Dart. Tully said that within the next year or so, Dart will begin running at least some of its cell-based assays in house.  
According to Tully, Dart currently targets genes that have been confirmed in experiments to be involved in various aspects of memory formation. The next step would be to incorporate these genes into cell-based assays in order to screen candidate small molecules in high throughput.
He also said that the exact nature of the cell line that is used in the assay depends on the nature of the target, and on the success of the target functioning in a particular cell line. As a result, it is “kind of hard to predict what exact cell line will be used in the end,” Tully said.
For high-throughput screening, it is not necessarily important to develop cell-based assays in a neuron per se, because usually, for example, if the gene target was a receptor, all one would need is a functional receptor expressed on the surface of a cell, said Tully. These cells are usually engineered to glow yellow or fluoresce in response to a ligand binding to the expressed receptor.

“The BioFocus DPI deal represents the first step that Dart Neuroscience is taking to assemble its own in-house compound library and begin screening novel targets.”

It is often a follow-up assay that is used with a small molecule hit to ask whether some function of a neuron is changed in response to exposure to that small molecule. That kind of follow-up assay would be done in house at Dart, said Tully.
It is expected that BioFocus will take between 22 and 27 weeks to develop the assay for Dart’s target and build the drug library, at which time there should be one or more confirmed hit presented from the library screens, said Kate Hilyard, vice president of biological sciences at BioFocus.
As part of the second component of the agreement, BioFocus will assess the quality of the 200,000 compounds and manage them in a custom library for Dart. The deal involves occasionally plating the compounds out into the 1,536 plates that it uses for its screening robots, Tully said.
Tully said that since the compounds are commercially available, Dart is not interested in the IP surrounding them. What usually happens is that a fair amount of medicinal chemistry must be done to analog away from an initial hit. One of the strategies that gets incorporated into such medicinal chemistry activities is to move toward analog structures that may fall outside of existing patents and disclosures.
“It is in the act of doing subsequent medicinal chemistry on initial hits that we hope to identify proprietary structures against those targets,” Tully told CBA News. He added that the company hopes to identify small molecules against novel targets that will facilitate some aspect of memory formation or cognition.
Speak, Memory
Tully was a professor at Cold Spring Harbor Laboratory for 15 years, where he studied learning and memory. From that research, he co-founded Dart and Helicon Therapeutics, which began trying to capitalize on the new information being discovered about how memory formation occurs.
“As we better understand the biochemistry of memory formation, we begin to see that aspects of memory formation are defective in various types of cognitive dysfunction, including age-related memory impairment and even some cases of mental retardation,” Tully said.
The purpose of Dart and Helicon is basically to get into the small molecule-development area with this knowledge in hopes that “we can identify novel therapies to treat these various aspects of memory impairment.”
“We think we should have a therapeutic application for” any diseases that show a component of memory impairment, said Tully. For example, a large fraction of Parkinson’s patients have memory impairment. According to the Parkinson’s Foundation web site, Parkinson’s disease affects, among other things, memory, executive function, attention span, mental processing, language, and visual-spatial processing. Such cognitive changes affect, to a certain extent, almost every Parkinson’s patient.
Dart, which currently has nine employees and expects to be “up to 30” by the end of 2009, according to Tully, is sort of “starting from scratch” in its research with BioFocus. Its primary focus is on validating the gene targets and then developing assays and doing the high-throughput campaigns. So one can imagine “the end of the spectrum where we will be doing most of the hiring” — including neurogenetics, assay development, cell biology, high-throughput screening, and compound acquisition and management.
Tully said the company anticipates that sometime near the middle of 2009 it will be “up to speed” in screening its library, and obtaining confirmed hits from those screens, which would “put us into the mode where we start building a medicinal chemistry group,” to do the hit-to-lead chemistry that is involved in this kind of approach.
Tully said Dart hopes to identify favorite molecules involved in various aspects of cognitive dysfunction, and cherry-pick the best ones and develop them in house.
“We are also trying to optimize the efficiency of high-throughput screening, which we understand will produce more hits from more targets than we would be capable of developing ourselves in-house,” so the company also anticipates a very vigorous out-licensing program with lead compounds that are high-throughput- and medicinal chemistry-developed over time, he said. 
The targets that Dart is interested in will also be of interest to other companies working on these areas of CNS disease. “What we are beginning to see is an overlap in the genes involved in memory formation, and genes that are thought to be defective in other aspects of CNS dysfunction,” said Tully.
By focusing on those overlapping genes, Dart can both identify small molecules for in-house development, and identify small molecules that would be of interest to other companies for out-licensing.
Dart will own all of the rights to the assays developed during the agreement, and BioFocus will have a nonexclusive right to use those assays to continue its work with Dart, said Tully.

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