For the last ten or fifteen years, untold amounts of time and money have been spent developing drugs to inhibit kinase enzymes. Just go take a look at KinasePro’s archives; that’ll give you the idea. Huge programs have been run at all the major drug companies, and any number of smaller ones have been founded just on the strength of one kinase inhibitor or another.
The enthusiasm isn’t hard to understand. For those of you outside the med-chem / biochem worlds, kinase enzymes are there to stick phosphate groups into other molecules, which is a very widely used signaling pathway. A phosphate completely changes the character of the part of a molecule where it’s attached, changing what other partners it will recognize and bind to. This takes place generally on to some sort of free OH group. That doesn’t narrow things down much, though, since there a lot of incredibly important small molecules with OH groups that get phosphorylated. Adding to the fun, several amino acids (serine, threonine, and tyrosine) have OH groups on them, and the means that nearly every decent-sized protein has plenty. The patterns of their phosphate groups turn their activities on and off, determine where they go and what they’ll recognize. It’s a major, major switching mechanism for protein activity – you can’t overstate its importance. Here's the classic family tree of the protein kinases, just to give you the idea. (And in case you’re wondering, there is indeed a whole different class of enzymes, the phosphatases, that take the things back off again - whole different bag of snakes, those guys).
There are hundreds and hundreds of kinase enzymes, and I think it’s safe to say that they’re involved in just about every important biochemical process you can think of. The downside of working on them is that, well, they’re involved in just about every important biochemical process you can think of. (Try this on for size, or this, to get the idea). How do you get them to do what you want?
Well, we’re still not sure about that. I go back far enough to remember when kinases were considered nearly impossible to work with as drug targets, because no one could figure out how you’d get selectivity. But once we figured out how to make molecules that recognized the “hinge” region common to most of these enzymes, the game was on. You can make blunderbuss molecules that inhibit dozens of enzymes at the same time, or (in some cases) you can narrow down on a mere handful, or on just one.
But how far do you want to go? That’s where we’re “over-asked”, as the German expression translates. The downstream effects of many of these enzymes are absolutely bewildering in normal cells, and the differences in disease states are even more of a tangle. It’s no surprise at all that most kinase inhibitors have shown up first in oncology, because that’s where you can get away with the most severe side effects. There are plenty of tempting opportunities in inflammation, diabetes, cardiovascular disease, and other areas, but those have been slower to come along.
The experience with the cancer-targeting drugs has been mixed. You have your Gleevec (imatinib) – pretty selective, works pretty well on a very limited group of patients. And you have your hand grenades, like Sutent (sunitinib) or Nexavar (sorafenib), which hit a lot of kinases and work (to some degree) on a lot of different things. But none of them are magic bullets, for sure. So do you want selectivity or not? The only answer we can offer is (still) “that depends”.
These days, there’s a distinct “kinase hangover” in the industry. It’s not as hot a field as it was. “Not again” is the usual feeling on seeing yet another patent or publication on yet another structure that inhibits XYZ kinase. It’s not as hot an area as it was a few years ago – the belief is that many of the best targets have either wiped out in the clinic, are being tried there now, or haven’t yielded reasonable chemical matter to even get there.
My guess is that we’re waiting, whether we know it or not, for our understanding of the biology to catch up. We have all these compounds, with all these different fingerprints, and we’ve generated this huge pile of mixed data that we can’t quite make sense of. That adds to the frustrated “been there” feeling. The cure for it is to have a better idea of what we’re doing and why, but that’s coming on much more slowly. And because that’s slow, the kinase field may never regain its hot status. But who knows, it may make it all the way to useful and valuable, bypassing “hot” completely.