The Right Kinase

Plexxikon's drug candidate for melanoma, PLX4032 (green), binds to the kinase B-RAF (yellow). Image Courtesy of Gideon Bollag

Today I posted a news story about the debut of the structure of PLX4032, a promising melanoma drug developed by Berkeley, California startup Plexxikon. This drug’s story has already been given the narrative treatment courtesy of the New York Times. And when the results of a Phase I clinical trial of PLX4032 came out, it got covered in many other news outlets as well. But we here at The Haystack are most interested in PLX4032′s chemical backstory. And when I contacted kinase expert Kevan M. Shokat for his opinion on the work, he said the story has another dimension- clues about how to pick the right kinase targets to treat diseases.

The kinase enzyme that Plexxikon’s experimental drug targets is called B-RAF. It’s part of a critical signaling pathway that also includes the kinases MEK and ERK. What’s interesting about Plexxikon’s stunningly successful early trial (81% of patients taking PLX4032 saw their tumors shrink) is just how well people tolerate the drug, Shokat says. The patients in that 81% success group were taking almost a gram of the stuff, twice daily. This is despite the obvious central importance of the RAF-MEK-ERK pathway, and in contrast to what happens when you block MEK, just one step down the pathway, Shokat says. Compounds that block MEK tend to have what’s called a narrow therapeutic index- there’s a small window between giving an effective dose and giving a toxic one, he says. So if researchers could understand why such a dramatic difference exists, it could help them make the right kinase choices for other diseases as well, he says.

When I spoke with Plexxikon’s senior VP of research, Gideon Bollag, he too had interesting things to say about kinases, but our discussion was less about choosing one kinase out of many and more about making the commitment to choosing one at all. “Over the last 10 years or so many of the drugs for cancer have been multitargeted kinase inhibitors, and I think our compound is changing that paradigm,” he says. “More selective compounds can be more effective because you can dose higher levels safely,” he says.

Author: Carmen Drahl

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1 Comment

  1. “I think our compound is changing that paradigm”

    Kudos to Plexxikon, but I never understand why this has to be an either/or proposition. I am sure that in some cases multitargeted inhibitors are better and in others it’s highly selective ones that can do the job. I get a little wary when people try to define “paradigms” for complex systems that don’t lend themselves to any one kind of approach.