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Researchers Using GSK Inhibitor Set to Explore Understudied Human Kinases


NEW YORK(GenomeWeb) – Leveraging a set of small-molecule kinase inhibitors developed by GlaxoSmithKline, a team of researchers from institutions including GSK and the Structural Genomics Consortium (SGC) aims to spark investigations into historically understudied portions of the human kinome.

In a study published this week in Nature Biotechnology, the researchers introduced the Published Kinase Inhibitor Set (PKIS), a collection of 367 inhibitors released by GSK for use in the project. In addition to describing the set, the study demonstrated a number of potential applications, including use of the compounds in the development of high-quality probes to less studied kinases.

Development of such probes is one of the primary purposes for which the SGC hopes to use the inhibitor set, William Zuercher, a researcher at University of North Carolina at Chapel Hill and senior author on the paper, told GenomeWeb.

Formerly a senior scientific investigator at GSK, Zuercher noted that while the set's compounds themselves are unlikely to work as high-quality probes, they provide structural insights and starting points for researchers developing such reagents.

"What we hope to do is take some of the hits against lesser studied kinases and do iterative chemistry to optimize their potency, their selectivity, and cell penetrance and produce new probes against these historically understudied kinases," he said.

The researchers provided in the paper an example of such an effort, using the inhibitor SB-633825 to help generate probes to the kinases LOK and SLK, both of which, Zuercher said, were relatively understudied.

Designed to target the kinase TIE2, SB-633825 also appeared to inhibit LOK in a screen performed by the researchers as part of the study. Given that LOK and SLK are close homologs, it was thought that the original SB-633825 agent could be used as a starting point for iterative chemistry work aimed at generating quality probes to these two proteins.

Zuercher and his colleagues tested 20 derivatives of SB-633825 against the kinases LOK, TIE2, and p38α, identifying two compounds that inhibited LOK while not exhibiting any activity against TIE2. They also identified another compound, GSK3037619A as an even stronger inhibitor of LOK and SLK.

The researchers have since done a round of iterative medicinal chemistry to improve the compounds' selectivity, Zuercher said. "To be bonafide probes we would have to improve their potency and do a little more optimization. But that is the goal."

He noted that while the SGC was not only looking to the GSK compounds in its probe development efforts, the large amount of data on these agents generated by the group and its collaborators as well as by GSK is helpful in prioritizing compounds for investigation.

In the Nature Biotechnology study, researchers screened the 367 inhibitor set in activity assays against 224 recombinant kinases and 24 G protein-coupled receptors. They also screened them in cellular assays using the National Cancer Institute's NCI-60 cancer cell line collection to test their effects on cancer cell proliferation and in another assay looking at their effects on angiogenesis.

Using this biochemical activity data and cellular data, the researchers now hope to further evaluate the inhibitors' effects using tools like phosphoproteomics or chemoproteomics that could help identify specific kinases or groups of kinases responsible for various phenotypes, Zuercher said.

"We want to associate [particular kinases] with interesting phenotypes to define potential kinases for therapeutic targeting and define new opportunities for [kinase inhibitors]," he said.

He noted that while there are some 500 protein kinases in humans, only around 10 percent have been studied in depth as potential drug targets — despite the fact, he said, that kinase inhibitors have proven to be one of the most successful classes of drugs in recent years with almost 30 such drugs now approved.

"We had this weird skew in the focus of research where everyone was working on things that we already knew a lot about and then the remaining 80 to 90 percent of the protein kinase family wasn't getting any attention at all," Zuercher said. "And this was a dynamic that had inertia, and it seemed that nothing was going to change in terms of focusing on those historically understudied kinases unless we did something different."

This dynamic, he said, was the impetus for putting together the PKIS, the idea being that looking at a large number of inhibitors covering various classes of kinases could inform research into lesser studied proteins.

"The idea there was to leverage the chemical connectivity of the inhibitors, because inhibitors of one kinase can often be used to identify inhibitors of other kinases," Zuercher said. "And we thought that if we released the set that we would be able to identify inhibitors or chemical starting points for inhibitors of kinases that hadn't been historically studied."

"It has been shown in a number of contexts that often if there is a high-quality small molecule inhibitor available, it can really lead to an inflection point on research on a particular target," he added.

The researchers convinced GSK to make the compounds available by establishing the PKIS as a public resource where no intellectual property or patent claims can be made on findings arising from research using the set.

The agents comprising the set had already been published on by GSK, Zuercher said. "On some level this is an experiment to see if it is the case that [the compounds] will have more value [as the PKIS] than they would if they just sat on the shelf at GSK."

"We really strongly believe that there is gold in terms of therapeutic opportunity embedded in this historically understudied kinome," he said.

However, he noted, convincing outside funding agencies and authorities inside pharma to provide money for looking into these proteins is a challenge.

"You need to build a case and talk about what has been done before and give the rationale for a specific target, but you can't do that if a target hasn't been studied before," Zuercher said. "One of the worst things you can be called [by a funding agency] is a fishing expedition," he said. "But, essentially, we're trying to catch fish here, so that is what we need to do."