My post the other day on a very unattractive screening hit/tool compound prompted a reader to mention this paper. It's one from industry this time (AstraZeneca), and at first it looks like similarly foul chemical matter. But I think it's worth a closer look, to see how they dealt with what they'd been given by screening.
This team was looking for hits against PIM kinases, and the compound shown was a 160nM hit from high-throughput screening. That's hard to ignore, but on the other hand, it's another one of those structures that tell you that you have work to do. It's actually quite similar to the hit from the previous post - similar heterocycle, alkylidene branching to a polyphenol.
So why am I happier reading this paper than the previous one? For one, this structure does have a small leg up, because this thiazolidinedione heterocycle doesn't have a thioamide in it, and it's actually been in drugs that have been used in humans. TZDs are certainly not my first choice, but they're not at the bottom of the list, either. On the other hand, I can't think of a situation where a thioamide shouldn't set off the warning bells, and not just for a compound's chances of becoming a drug. The chances of becoming a useful tool compound are lower, too, for the same reasons (potential reactivity / lack of selectivity). Note that these compounds are fragment-sized, unlike the diepoxide we were talking about the other day, which means that they're likely to be able to fit into more binding sites.
But there's still that aromatic ring. In this case, though, the very first thing this paper says after stating that they decided to pursue this scaffold is: "We were interested to determine whether or not we could remove the phenol from the series, as phenols often give poor pharmacokinetic and drug-like properties.". And that's what they set about doing, making a whole series of substituted aryls with less troublesome groups on them. Basic amines branching off from the ortho position led to very good potency, as it turned out, and they were able to ditch the phenol/catechol functionality completely while getting well into (or below) single-digit nanomolar potency. With these compounds, they also did something else important: they tested the lead structures against a panel of over four hundred other kinases to get an idea of their selectivity. These is just the sort of treatment that I think the Tdp-1 inhibitor from the Minnesota/NIH group needs.
To be fair, that other paper did show a number of attempts to get rid of the thioamide head group (all unsuccessful), and they did try a wide range of aryl substituents (the polyphenols were by far the most potent). And it's not like the Minnesota/NIH group was trying to produce a clinical candidate; they're not a drug company. A good tool compound to figure out what selective Tdp-1 inhibition does is what they were after, and it's a worthy goal (there's a lot of unknown biology there). If that had been a drug company effort, those two SAR trends taken together would have been enough to kill the chemical series (for any use) in most departments. But even the brave groups who might want to take it further would have immediately profiled their best chemical matter in as many assays as possible. Nasty functional groups and lack of selectivity would surely have doomed the series anywhere.
And it would doom it as a tool compound as well. Tool compounds don't have to have good whole-animal PK, and they don't have to be scalable to pilot plant equipment, and they don't have to be checked for hERG and all the other in vivo tox screens. But they do have to be selective - otherwise, how do you interpret their results in an assay? The whole-cell extract work that the group reported is an important first step to address that issue, but it's just barely the beginning. And I think that sums up my thoughts when I saw the paper: if it had been titled "A Problematic Possible Tool Compound for Tdp-1", I would have applauded it for its accuracy.
The authors say that they're working on some of these exact questions, and I look forward to seeing what comes out of that work. I'd have probably liked it better if that had been part of the original manuscript, but we'll see how it goes.