A reader sends pointed me to this paper, whose title they found interesting: “Characterization of a Steroid Receptor Coactivator Small Molecule Stimulator that Overstimulates Cancer Cells and Leads to Cell Stress and Death”. An unusual mechanism, for sure – so what is this compound, exactly?
You have to go into the Supporting Information to find that out. “MCB-613” was identified in a cellular screen with compounds from a Molecular Libraries Probe Production Centers Network collection. And when you track down the structure, well, there you have it: yet another bis-chalcone. Whoever produced a library of those things really ripped off the funding agencies, that’s for sure.
What’s a bit annoying and concerning is that the paper just takes the structure and runs with it. There’s no mention of the fact that it might not be very drug-like, and that it might be reactive. The paper has a lot of painstaking work in various cell assays to try to work out the effects of the compound, and includes some SPR assays that seem to show reversible binding to one component of the nuclear coactivator SRC-3. But there are a lot of things that a structure like this can do, and there seems to be no recognition of this. It’s a compound, and it hits, and what else do you want? They mention that it’s a chalcone, but as a feature, because lots of chalcones are bioactive, and so on.
There’s similar stuff in this recent J. Med. Chem. paper. The authors have been working in this area for quite a while now, and they’ve not only got the bis-chalcone, but both aryls are Mannich products as well. This is a festival of problematic functional groups, to be honest. And the paper has plenty of cellular activity data, with (as in the other paper) some apparent selectivity between tumor cell lines and more normal ones. But still.
These structures have a very low probability of ever being drugs – I suppose that’s what I’m trying to get across. Now, there are a lot of unlikely chemotherapy drugs out there (nitrogen mustards being one vicious example), and structures like this could possibly still find a use. But there are a lot of assays that would need to be done in order to shore things up a bit. For example, doing a whole-proteome screen to look for covalently modified proteins would be a good idea, since you’d really expect something like that to be going on.
And that’s not even getting to the big question: in vivo. It’s one thing to show effects against tumor cell lines in culture, but the real challenge for these kinds of structures will come when they have to be dosed in an animal. The J. Med. Chem. paper talks about these as “lead preclinical drug candidates”, but nothing’s really a drug candidate until it’s been in animals, not to put too fine a point on it. I know that’s a completely different realm than the authors of these two papers are working in, but – how to put this? – the numbers of compound that kill tumor cells are almost beyond counting. It’s not that high a bar to clear, and if you’ve got something interesting, it needs to be taken through those next steps, rather than (say) have another thirty-four cell assays run on it. An awful lot of work has gone into this sort of chalcone chemistry over the years, partly because you can make a lot of compounds very quickly. But what’s come out of it?