Magazine
Two Ends of the Hallway
By Derek B. Lowe
One end of the hallway:
Look at these projects, just look at ‘em. Some of them have been going on for years now; the people on them have forgotten what a deadline looks like. XYZase over there, they’ve been telling me since 2006 that they’re just about to deliver. It was just the PK, they told me – the compound just needed a long enough half-life. Then it was just that pesky rat tox, which basically showed up once they got a compound to hang around long enough. Now they’re worried about their IP, because the project’s been going on so long that someone else has filed right up next to their own chemical matter. Sheesh. I’d kill the whole thing if we weren’t planning on it to make the departmental goals this year. You know, just like we’ve been every year since 2006. If it ever does deliver and get out of my department, I’ll probably start missing it.
ABCase: now there’s another one. What a target! What a model! What a screening cascade! What a sinkhole, if you ask me. It took forever to get a protein construct good enough to run an assay with, and then we had one of those hit rates that make you wonder if we own anything that doesn’t bind. But nothing stood out. It was Dawn of the Dead, a list of all the stuff that had slipped down under the seat cushions over in the HTS group. So the hit-to-lead people didn’t know where to even start, which gave the biologists time to work up the most wonderful set of in vitro assays you ever saw. Any compound that goes through them all hops around like a Pomeranian in a circus dog show: In the enzyme, around the three counter-assays, dive into three different cell lines, bing bing bing.
And what comes out the other end? Not much, so far. But boy, does it make a great presentation. If anything ever makes it through all that machinery, it’ll be some kind of compound, but so far everything’s been ground to dust about halfway through. The project’s not going away, though, not after everyone over in the other building spent so much time building the Perfect Drug Discovery Beast. But you’ve got your choice on this one: Lots of Compounds (most all of which are likely junk) or No Compounds At All (but they’re all perfect).
Oh, we’ve got ‘em all here. The people over in the other therapeutic areas are proposing targets for slow-moving diseases that have no animal models — well, no models that anyone believes. “Think of the unmet medical need,” they say. “Think of the market share!” All I can think about is our axles buried deep in the mud. It’s like that Alzheimer’s program we had — they kept giving me flak because we didn’t deliver for so long, then the Clinical people fled in terror when we actually came up with a compound. It’s enough to think I should have gone to dental school. How exactly did I end up managing a department whose success depends so much on luck, and so much on things that we don’t understand?
The other end of the hallway:
I tell you, this time of year I look at the departmental goals around here and I think that we need to check the corner offices for radon levels. Exhibit A: XYZase is supposed to deliver by the end of the third quarter. Third quarter of what year? They’ve been giving us “just one more quarter” deadlines on that one for the past two years, so you can imagine the sorts of things that get done – if you can finish it off in two weeks, you do it, and if you can’t, you don’t even bother to start. Then all of a sudden it’s six months later, and you find that you’ve been living the whole stretch in two-week chunks.
No wonder the thing looks like it does. For a long time, everyone wanted to see Potency, Potency at all costs! So we gave ‘em potency, and we paid for it the usual way — by strapping big hydrophobic water wings onto the original scaffold. None of the better-looking compounds ever made the activity cut, and you don’t get much credit around here for making reasonable compounds if they don’t work. Ugly nanomolar ones, on the other hand, seem to be just fine — those are Progress, y’know.
Then when we met the mighty potency goal, and could finally get some animal slots, we saw. . . well, just what you’d figure we’d see: PK numbers that would curl your hair. So then the whole thing turned into a PK-driven project, which meant that we had to make big ol’ piles of compound every time we wanted to test something, which was a real joy. We’re right back to the keep-taking-shots method of drug discovery, only this time we can only do a handful of compounds a month.
We finally got the half-life we needed, without burning off too much of the activity doing it, and in we went for two-week tox (after first making the biggest bucket yet of the compound, and didn’t that thiol step just make us the most popular people upwind of the department?) And by gosh, rat tox showed us that the compound is . . . toxic to rats! But at the doses we’ve had to go up to, you probably couldn’t get granola bars through a two-week tox. At least you don’t need propanethiol to make those. I think.
And then you’ve got those poor folks on the ABCase project. They haven’t had to worry about rat tox and all the rest of it, but at the rate things are going, they probably never will. All those micromolar compounds, no way to pick among ‘em, and management is constantly jumping on the team to stop messing around, settle down and pick something. Pick what? And pick how?By drawing compounds out of a sack? Nothing really shows much SAR, so after a while, that sack starts looking like a pretty good option. And meanwhile, the biologists think it’s the greatest target they’ve ever seen, so they keep wondering why the chemists aren’t sending over lots of great compounds. So no, I don’t think I want to work on that one, although it’s sure to still be going once we police off XYZase.
But if it’s not that one, then where? I have to say, the rest of the new targets coming up look kind of weird. Not sure if we’re going to get a lot of chemical matter for those guys — and if we do, odds are it’s going to look kind of like the chemical matter we already have, because guess what makes up most of the screening file? At least I already know how to make those things; that’s a plus. But it does make you wonder how I ended up working on projects whose success depends so much on luck . . .
