TWO YEARS ago, while serving as executive vice president in charge of separations products at Dyax, Robert Dishman realized he had to find a way to get involved in the blossoming field of proteomics. With a PhD in chemistry from the University of Massachusetts, Amherst, where he made a specialty of high-performance liquid chromatography, he could see that proteomics had the potential to contribute to speeding the timeline of drug discovery.
The problem for Dishman was that Dyax was headed in other directions. Henry Blair, Dyax’s chairman and CEO, planned to keep the company focused on using phage display technology to identify potential protein and antibody therapeutics, leaving little room for Dishman to explore other proteomics-based techniques for discovering new targets and drugs.
But then Dishman met Timothy Haystead, who at the time held a faculty position in the department of pharmacology at the University of Virginia. Haystead had developed a technique for immobilizing a class of purine-binding proteins to an affinity column using ATP as an affinity agent, and he came to Dishman at Dyax in search of a multichannel chromatography system that he could use to screen the proteins immobilized on the column for interactions with specific small molecules.
To Dishman, who had also founded combinatorial chemistry company Arqule in 1990, this represented a critical opportunity. Together with Haystead, now a professor of pharmacology at Duke University, he raised $3.5 million in venture funding — partly from Mediphase Venture Partners, a fund Dishman works with as a partner — and licensed Haystead’s technology from U.Va. They then set up shop in Durham, NC, to industrialize the technology for applications to drug discovery. They called the company Serenex because they hoped the technology would lead them to serendipitously discover new drugs and drug targets.
The technology has the potential to do this, Dishman recently told ProteoMonitor, because of two aspects of the company’s core technology. Haystead’s technique uses ATP immobilized to an affinity column to select out only purine-binding proteins from cell lysates. This allows the company to exclusively study a class of proteins rich in “druggable” targets, such as kinases, metabolic proteins, and heat shock proteins, Dishman said.
Furthermore, Haystead developed a method — also licensed by Serenex — for screening that library of purine-binding proteins using small molecules or other drug-like compounds. If the small molecule displaces one or more of the proteins bound to the column via ATP, Serenex applies its mass spectrometry platform to identify the one or more potential targets.
Drug discovery often works the other way around, with scientists first identifying the function of a target before developing a small molecule. But Serenex, now with 18 employees, hopes to use the technology to help drug companies refine the structure of their drug candidates to make them specific to only the desired target. Knowing what other proteins the candidate inhibits can aid medicinal chemists in refining the chemistry of the drug, Dishman contends. “We look up [the proteins using mass spectrometry] to see if they’re known or interesting targets,” he said. “We can then try to find out whether we’ve discovered a target and a lead, as well as [that lead’s] specificity.”
Dishman also said the technology has applications for helping pharmaceutical companies identify the cause of a drug’s toxicity. If proteins in addition to the desired target elute off the column when exposed to a small molecule, these proteins could potentially be involved in the pathway responsible for a patient’s toxic reaction.
Although Serenex is less than a year old, several large pharma companies, as well as several biotech companies, have agreed to small trial projects with the startup to check out its technology. With one New York-based big pharma, Serenex is studying three potential drug compounds, and has already identified several “off targets” that could be responsible for the compounds’ toxicity profiles, Dishman said. With the other big pharma customer, Serenex is studying purine-binding protein targets associated with 10 potential drug candidates, he said.
In addition to fee-for-service contracts, Serenex is also establishing its own infrastructure in drug discovery and development. As its first solely-owned project, Serenex is looking to develop drugs against a target associated with rheumatoid arthritis that Haystead discovered in his academic lab. Also, because Dishman has structured his deals with Serenex’s pharma and biotech partners to allow the company to share intellectual property rights to additional targets discovered during the course of the contract research, the company plans to build a medicinal chemistry team of 25 scientists to develop small molecules against any targets Serenex’ pharma partners decide not to pursue.
“If we discover a new target, we own 50 percent [of the IP], although the pharma or biotech has the right of first refusal,” Dishman said. “If they put $500 million into drug development, then our share [of the IP] goes down, but not below [something like] 10 percent,” he said.
To finance its drug development capabilities, Dishman is currently sewing up the loose ends on another round of financing, an amount that he said is substantially greater than the first round of $3.5 million. In addition to hiring chemists, the money will go toward the purchase of an Applied Biosystems MALDI TOF-TOF and the design and implementation of robotics from Tecan and other suppliers to automate the imaging, spot-picking, and digestion of proteins separated by 1D gels. The TOF-TOF, to be delivered in June, will complement Serenex’s electrospray ABI QSTAR Q-TOF, Dishman said.
— JSM