When the topic of “frequent hitters” in drug screening comes up (PAINs, promiscuous compounds, whatever you’d like to call them), the literature divides into two general camps. I don’t think they’re of equal size, but still. . .the larger one is the one that I caucus with, the one that says “These things need to be watched carefully, because they have an excellent chance of wasting your time”. But there’s another group, typified by the paper discussed here, who look at these structures as a real opportunity. So much activity! Hitting targets that nothing else can reach!
A new paper in Drug Discovery Today makes just this case: “Filtering promiscuous compounds in early drug discovery: is it a good idea?” Their big objection is that many compounds act polypharmacologically, and that filtering out PAINs only makes sense if you’re thinking one-drug-one-target, or perhaps they’d say still stuck thinking that way. They especially recommend not filtering if you’re doing phenotypic screening, and point out a number of known drugs that would have been filtered out.
I’m unconvinced. Doxorubicin, for example, is brought in to make the case for quinones. And while it’s certainly true that it’s a valuable chemotherapy drug, it’s also true that cancer chemotherapy is one of the few places where it would be part of the pharmacopeia. It’s toxic stuff. The other therapeutic areas where you find quinones also tend to be massive-attack situations (antiinfectives) or topical agents. It’s very hard to dose something like that systemically and not run into trouble. Not impossible, to be sure – just very difficult, and you have to weigh those chances of success versus what else you might have to work with.
The authors also take care to distinguish many forms of assay interference from such in vivo problems, which is fine. Fluorescent interfering compounds, aggregators, and the like are trouble no matter what, and you need to run the appropriate controls to make sure that you don’t go chasing after them. (The lower the intrinsic hit rate of your assay, the greater the danger of this kind of thing). Still, some of these mechanisms are related. Redox-active compounds can be trouble in the assay well, and trouble in the whole animal, too, for similar reasons.
This paper calls frequent-hitter chemical classes “Bright Chemical Matter”, referring to the “dark chemical matter” discussed here. Those are the compounds that hit very rarely in screens – which, interestingly, are hard to distinguish from a lot of the stuff that does hit.
It was suggested that DCM is in fact made of nonpromiscuous molecules that can occasionally demonstrate activity in specific biological assays. Thus, DCM could potentially have unique activity and clean safety profiles, making DCM a valuable starting point for lead optimization efforts . The reciprocal is true: molecules that frequently have a biological effect on diverse assays, but do not act as bioassay interference compounds, although challenging, can be optimized into innovative and safe drugs under the premises of new conceptual frameworks such as systems biology and polypharmacology. Here, we propose referring to these privileged molecules with high biological activity as bright chemical matter. . .
The paper goes on to say that (in the authors’ view) such compounds can be optimized into useful drugs, especially if you’re looking for (or not selecting against) polypharmacology. I’m not denying this, but I am pointing out that this approach does give you a greater risk for failure. I suppose there are two ways of looking at this: you could say that our failure rates are so high already, that what’s a bit more? Or you could say that our failure rates are so high already that piling on even more risk is the last thing you’d want to do. My worry is that giving these compounds a name like “bright chemical matter” (which I really hope doesn’t catch on) makes them actually seem desirable instead. Even the authors here don’t go that far.
An interesting contrast to all this can be found in another new paper, from Jonathan Baell (who originated the PAINs acronym and has published widely on the concept). He’s looking at natural product structures that overlap with known promiscuous-activity motifs. As he points out, these quinones, catechols, Mannich bases and so on don’t lose their reactive character just because they happen to be found in natural products. In fact, many of them have probably been evolutionarily selected for just those shotgun properties. (They’re also typically sequestered in the cell, excreted, or produced in transient amounts if they’re used as signaling molecules). Says Baell:
As was the case for catechol-containing drugs, the quinone PAINS moiety can still display PAINS behavior even if it is embedded in a drug, and whether or not it is a natural product, and this behavior may contribute paradoxically to both efficacy and toxicity. Discovery of quinone-containing drugs once again arose from early observation of useful in vivo efficacy or potent cell-based activity at therapeutically relevant concentrations or close to thereof, prior to knowledge of mechanism of action. So once again, the utility of these compounds in humans does not represent a modern and rational progression from upstream assays to downstream assays and eventually to clinical use. No connection should be made between a quinone-containing screening hit and a quinone-containing drug. The PAINS behavior more or less universally exhibited in quinones should render them deemed to be unprogressable as low micromolar potency screening hits, whether in a target-based assay such as Kv1.3 described here, or a phenotypic assay.
Here’s where these two papers overlap. But Baell’s makes the point that compounds like doxorubicin were discovered in phenotypic assays already acting at the potency needed. If you’ve got a red-alert PAINs-type structure as a hit, it had better blow out your assay. The huge majority of the drugs containing these structures were found by direct in vivo screening, and were active at clinically relevant levels right from the start, not as micromolar leads that were going to be the foundation for a development program. But that’s where you see the great majority of PAINs in the literature now: micromolar stuff presented as promising leads against difficult targets. Optimizing these is not an impossible task (as the authors of the Drug Discovery Today article would be quick to say), but neither is it a very good bet (as Baell would say, and so would I). Just because doxorubicin is a valuable drug doesn’t mean that the 30-micromolar quinone that just came out of your protein-protein screen is a worthwhile lead compound. You’re facing some of the longest odds in the business if you try it.