Catch Me If You Can

By: Peri Zundell  |  December 1, 2016
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Do you know what it’s like to chase after someone playing hard to get? For decades, that’s exactly how researchers felt about KRas, a cancer-causing protein. Fortunately, researchers have finally made some progress in developing pharmaceutical drugs to target this ever-elusive protein. They haven’t quite “gotten the girl” yet, but they are cautiously optimistic.

Initially, when researchers saw that they weren’t getting very far with KRas, they moved on to other lines of research. They turned towards developing molecules to treat cancer-targeted protein kinases, which connect other proteins with phosphate groups. Unlike KRas, kinases are much more easily targeted by drugs. Kinase activity is quite easily turned off when other small molecules bind to it, thereby removing their ability to function. But, at some point, scientists began to feel like they had exhausted kinase research and turned their attention to KRas once again.

The breakthrough? In 2011, chemist Kevin Shokat and his lab discovered a shallow pocket on a version of the KRas protein which is known to be a major driver of lung cancer. This was a pretty big deal, because scientists use the unique and complex shapes of proteins in order to target them. Researchers had likened the KRas enzyme to a billiards ball with regard to its smoothness, making it difficult to design molecules that could bind to it. However, with the discovery of this shallow pocket, the scientists in Shokat’s lab were able to discover the first covalent inhibitor of the protein.

Dr. Shokat isn’t the only scientist that has started to see some progress. Around the same time that he and his lab began their work, chemist Greg Verdine was also trying to find ways to inhibit flat proteins such as KRas. Dr. Verdine looked towards human biology for some inspiration. There are a number of examples in the body of proteins that can only block their targets with the help of an intracellular protein, such as the protein-folding chaperone FKBP. In 2012, Dr. Verdine launched Warp Drive Bio in order to develop drugs that would imitate this phenomenon by acting as a Velcro between the flat target protein and FKBP. Thus far, the project has made strides towards understanding the way these molecules interact with KRas and aims to have a drug ready for clinical trials by 2018, so stay tuned!

Some research teams are still ambitiously trying to directly target the active site on KRas itself. But these researchers face a difficult task. Many believe this will lead to a dead end, and some have even gone so far as to call this approach crazy. However, Dr. Ken Westover, who is currently working on the project, insists that they have the theoretical work and proof-of-concept sufficient to keep hopes alive. We’ll have to wait and see if his optimism will pay off.

Although there are more and more details about KRas emerging, researchers are well aware that they cannot really come to any conclusions until these drugs are tested on humans. It is yet to be determined which approach will be best tolerated and what side effects may occur. Candidates hope to have their drugs ready for clinical trials by 2018. Maybe, just maybe, researchers can catch KRas once and for all.

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