By Justin Petrone
Kinexus, a 10-year-old proteomics company based in Vancouver, BC, later this month will begin offering customers the ability to screen kinases using its internally developed microarray platform, according to a top official.
Steven Pelech, the firm's co-founder, president, and chief scientific officer, told BioArray News recently that the new kinase-inhibitor screening service will complement the firm's menu of Kinex antibody and reverse lysate microarrays.
Initially, the protein kinase chip will include "at least 200 different human protein kinases," Pelech said, though Kinexus plans to add more content as it identifies more kinases that will work with the platform. The 200 kinases on the array will be printed in triplicate in grids of 600, allowing users to test each subarray with a different compound or a different concentration of the same inhibitor, Pelech said.
According to Pelech, Kinexus' kinase inhibitor screening assay calls for the incubation of the array with the test compound of interest that is suspected to be an inhibitor. In response to this incubation, the drug candidate might bind directly with the active site of a kinase or it may induce a conformational change in the kinase that closes the active site, Pelech said.
When the unbound drug is washed away, the kinases that do not interact with the drug do not show any binding. For the kinases that do, though, the binding inhibits the accessibility of an active-site binding probe developed by Kinexus.
The probe, a biotinylated analog of ATP, is then covalently attached to the active kinases at a conserved lysine residue. If there is no drug bound and the kinase is exposed and active, the ATP probe binds to the kinase, Pelech said. The unbound ATP probe is then washed away and the chip is probed with fluorescently tagged avidin, which binds to the biotin.
"We can quantitate the amount of ATP that was bound to the kinase by virtue of the amount of dye that was on the avidin that was sticking to the biotinylated ATP," Pelech explained. "A reduction in signal indicates that this kinase can bind the drug, most likely at its active site."
Once kinases that are affected by the drug are identified, Pelech said Kinexus will offer in parallel an enzyme activity-screening service to follow up on those leads. He also said that the firm is considering using the chip for monitoring protein kinase-protein interactions and for identifying substrates of kinases that are themselves kinases.
"This can be insightful for mapping out the connections between kinases in signaling pathways," Pelech said. "We can use these kinase chips for determining the specificity of peptide substrates of kinases and pseudo-substrate inhibitors of kinases."
He said Kinexus believes that information could be useful for drug makers. "Over a third of all big-pharma R&D is targeting protein-kinase inhibitors," Pelech said. "Many of the kinase-based drugs that are presently in the clinic are not that specific," he said. "Ideally, drug companies want to discover inhibitors of kinases that are actually very specific for their target protein kinases.
"The more kinases they can screen against, the greater confidence they have that they are targeting the right kinases and that they are not getting off-target effects," he added.
"Most of the world's major pharma companies" use Kinexus' services, Pelech said, without elaborating. Still, big pharma isn't the firm's only target. Pelech said that Kinexus has worked with "over 900 academic labs in universities, hospitals and government institutes," as well "about 200 industrial labs."
One of the main factors in selling the service, Pelech said, will be the price. "Maybe about six years ago, you could easily be spending $50 to $100 per assay of an inhibitor against a kinase," he said. In recent years, that has dropped to the $5 to $10 range. By making triplicate measurements, Kinexus expects to offer its chip for around $1 per kinase analysis.
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"We think that now it is much more economical for companies to go out and screen a larger repertoire of kinase inhibitors against a larger number of targets and improve the prospect that they can identify more specific inhibitors," Pelech said. Since pharma may already have the drug in hand, "inhibitors that turn out to be even more potent against other kinases ... may be in fact quite interesting for them to pursue," he said.
There are a number of other companies courting similar customers with tools or services to screen kinases. San Diego-based Ambit Biosciences, for instance, is able to screen 442 kinases using its KinomeScan assay. Berlin's JPT Peptide Technologies offers an array-based kinase-profiling service, as does Houston-based LC Sciences and the Netherlands' PamGene.
For Kinexus, its new service will compete with those companies but expand on an existing portfolio of array-based services. In 2006, the firm launched an antibody-screening service, and in 2008 it began selling reverse lysate arrays, also as a service.
Pelech said that Kinexus has chosen to launch its chips via a service rather than as catalog products because it is "much cheaper for our clients to take by this route and it enables them to follow up much more effectively than if they were left to do it themselves."
According to Pelech, Kinexus' chips are produced externally by a number of partners. Its antibody arrays were developed with Genome British Columbia's microarray facility at the Prostate Research Centre at Vancouver General Hospital. The firm's reverse lysate arrays were developed with the National Council of Canada Biotechnology Research Centre in Montreal. Kinexus has worked with other companies to print its chips and has "multiple organizations and companies" that print its arrays depending on format, pricing, and other factors.
In addition to arrays, Kinexus also offers in vivo cell preparation, Western blotting services, immunohistochemistry services, bioinformatics support, and other services.
Now, Kinexus is "poised to split off into several different companies," Pelech said. The core company will continue to include proteomic services, which include array-based screening services. It will also include its bioinformatics division, which supports public databases like KiNET and PhosphoNET, as well as an emerging division called Biotools that will engineer new antibody and peptide probes to be used in new products, such as antibody arrays and peptide arrays.
"The rationale behind creating these divisions soon is that if we ever decide to sell Kinexus down the road, we may choose to sell the company in parts, as opposed to an aggregate," Pelech said. "We have no intention of selling our company for a few years, because I believe we can add a lot of shareholder value in the interim, but I thought it's a good idea to set up these divisions early."
Pelech added that Kinexus has developed protein microarray technology that "works well for biomarker discovery in preliminary studies for detection of Alzheimer disease with blood lymphocytes." To commercialize this platform, Kinexus will spin off a diagnostics company that it aims to have incorporated by the end of this year.
"They'll be looking at serum and blood samples and other types of bodily fluids for the ability to identify biomarkers using our antibody-driven methods as opposed to the mass spectrometry approaches that most other companies have adopted," Pelech said. Kinexus also plans to spin out another firm in a "few years" that will use its kinase inhibitor discovery platform to identify new drug leads, he said. He did not elaborate.
Pelech said that it is likely that different venture capital groups investing in these spin-outs will have majority control in the daughter firms. Still, Kinexus will probably be a "major provider of proteomics and bioinformatics services to these spin-outs, so initially they will not require wet labs," he said.