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May 28, 2014
Would You Have Advanced BBI608?
Over the weekend, Dainippon Sumitomo got some very bad news about a compound they were developing against cancer stem cells. It's BBI608, which they picked up by buying Boston Biomedical a couple of years ago, for pretty substantial money. The compound was in a colorectal cancer trial, but the first interim analysis of the treatment group was so bad that enrollment was stopped entirely.
Cancer stem cells - now that's a field with a lot of promise and a lot of risk. No one, it's safe to say, really understands what's going on there. And you can find some people who doubt the whole concept. Are there really pluripotent cells (a small population) driving some kinds of tumors? Evidence points that way, but getting a handle on them and figuring out their role has been hard. These latest results are not going to clear things up much, either.
I have to say, though, I would have been wary about shelling out $200 million up front for a compound that looks like this. That's BBI608 to the left, and yep, it's a big ol' quinone. I will freely admit my own biases here: I strike quinones (and their hydroquinone partners) off any list of screening hits I get. Life's too short. There are just too many things that can go wrong with dosing such an obvious, screaming, reactive redox compound in a living system. People who've worked with me can corroborate my statements; I've drawn red X marks through compounds that look a lot like this one and never looked back. Note that I am not saying that no quinones can ever be drugs. I'm just saying that the odds are stacked against them.
It's not like the activity you get is spurious - quite the contrary. Quinones can do a lot of things inside cells, which make them over-represented in cellular and phenotypic assays (assuming you let them into your compound collection in the first place). But those activities can change, depending on what sort of oxidative or metabolic stress the cells are under (and many other factors besides). BBI608 must have had some pretty compelling early-stage data to make Dainippon Sumitomo jump at the chance to buy it (and its company), but look at it now.
I wouldn't have even trusted this one as a tool compound, given the number of possible activities (even Boston Biotech kept taking about "inhibiting multiple pathways"). What kind of tool compound is it, given these clinical data? It's true that by tossing this structure into the trash that I wouldn't have had a company that got bought out for $2.6 billion dollars. And I wouldn't have had the satisfaction of taking a compound into the clinic with hopes of success, misguided or not (I haven't had that satisfaction too often, come to think of it). So there's that. But on the other hand, I've been working on things during that time that at least haven't failed yet, and the next molecule I do help push into the clinic will not, I assure you, look like this one, because I want to give it every chance I can to have it actually work.
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