A couple of years back, AbbVie ran into an unusual problem in the clinic. Their Bcl ligand, ABT-199, was working a bit too well, and killing off so many leukemia cells that the resulting cellular debris was causing kidney trouble in some patients. The company immediately started working on clinical protocols to get things restarted, and I’m happy to report that the compound seems to be meeting its endpoints in its current trial, and the company (and its partner Roche) say that they will be filing soon for FDA approval.
This will not only be a real step forward in chronic lymphocytic leukemia (CLL), and potentially several other forms of leukemia, lymphoma, and myeloma, it’ll be a real step for medicinal chemistry as well. These Bcl-targeted compounds are pure protein-protein interaction (PPI) inhibitors, a class of drug that’s historically been a hard slog. It’s still a tough way to make a living – the Bcl system has a very nicely defining binding groove in it, which helps – but over the years, more and more research organizations have been banging away at this sort of target. (Some have even been thinking about ways to do the opposite – making protein-protein interactions even more stable than they are already).
There are hundreds of thousands of these interactions going on in living cells. I don’t know what percentage of those are “druggable” (no one does), but we’ve only just begun to figure out how to do it. And I don’t know how many big, general discoveries are waiting in this area, because the variety of protein interaction surfaces is pretty impressive. But you can’t rule out such things, either. We know that PPI-based drugs are possible; now we could use some breakthroughs to make them a little more likely.