C&E News has a story today that is every medicinal chemist's nightmare. We are paid to find and characterize chemical matter, and to develop it (by modifying structures and synthesizing analogs) into something that can be a drug. Key to that whole process is knowing what structure you have in the first place, and now my fellow chemists will see where this is going and begin to cringe.
Shown at left are two rather similar isomeric structures. The top one was characterized at Penn State a few years ago by Wafik El-Deiry's lab as a stimulator of the TRAIL pathway, which could be a useful property against some tumor types (especially glioblastoma). (Article from Nature News here). Their patent, US8673923, was licensed to Oncoceutics, a company formed by El-Deiry, and the compound (now called ONC201) was prepared for clinical trials.
Meanwhile, Kim Janda at Scripps was also interested in TRAIL compounds, and his group resynthesized TIC10. But their freshly prepared material was totally inactive - and let me tell you, this sort of thing happens all too often. The usual story is that the original "hit" wasn't clean, and that its activity was due to metal contamination or colorful gunk, but that wasn't the case here. Janda requested a sample of TIC10 from the National Cancer Institute, and found that (1) it worked in the assays, and (2) it was clean. That discrepancy was resolved when careful characterization, including X-ray crystallography, showed that (3) the original structure had been misassigned.
It's certainly an honest mistake. Organic chemists will look at those two structures and realize that they're both equally plausible, and that you could end up with either one depending on the synthetic route (it's a question of which of two nitrogens gets alkylated first, and with what). It's also clear that telling one from the other is not trivial. They will, of course, have the same molecular weight, and any mass spec differences will be subtle. The same goes for the NMR spectra - they're going to look very similar indeed, and a priori it could be very hard to have any confidence that you'd assigned the right spectrum to the right structure. Janda's lab saw some worrisome correlation patterns in the HMBC spectra, but X-ray was the way to go, clearly - these two molecules have quite different shapes, and the electron density map would nail things down unambiguously.
To confuse everyone even more, the Ang. Chem. paper reports that a commercial supplier (MedKoo Biosciences) has begun offering what they claim is TIC10, but their compound is yet a third isomer, which has no TRAIL activity, either. (It's the "linear" isomer from the patent, but with the 2-methylbenzyl on the nitrogen in the five-membered ring instead).
So Janda's group had found that the published structure was completely dead, and that the newly assigned structure was the real active compound. They then licensed that structure to Sorrento Therapeutics, who are. . .interested in taking it towards clinical trials. Oh boy. This is the clearest example of a blown med-chem structural assignment that I think I've ever seen, and it will be grimly entertaining to see what happens next.
When you go back and look at the El-Deiry/Oncoceutics patent, you find that its claim structure is pretty unambiguous. TIC10 was a known compound, in the NCI collection, so the patent doesn't claim it as chemical matter. Claim 1, accordingly, is written as a method-of-treatment:
"A method of treatment of a subject having brain cancer, comprising: administering to the subject a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof; and a pharmaceutically accepted carrier."
And it's illustrated by that top structure shown above - the incorrect one. That is the only chemical structure that appears in the patent, and it does so again and again. All the other claims are written dependent on Claim 1, for treatment of different varieties of tumors, etc. So I don't see any way around it: the El-Deiry patent unambiguously claims the use of one particular compound, and it's the wrong compound. In fact, if you wanted to go to the trouble, you could probably invalidate the whole thing, because it can be shown (and has been) that the chemical structure in Claim 1 does not produce any of the data used to back up the claims. It isn't active at all.
And that makes this statement from the C&E News article a bit hard to comprehend: "Lee Schalop, Oncoceutics’ chief business officer, tells C&EN that the chemical structure is not relevant to Oncoceutics’ underlying invention. Plans for the clinical trials of TIC10 are moving forward." I don't see how. A quick look through the patent databases does not show me anything else that Oncoceutics could have that would mitigate this problem, although I'd be glad to be corrected on this point. Their key patent, or what looks like it to me, has been blown up. What do they own? Anything? But that said, it's not clear what Sorrento owns, either. The C&E News article quotes two disinterested patent attorneys as saying that Sorrento's position isn't very clear, although the company says that its claims have been written with these problems in mind. Could, for example, identifying the active form have been within the abilities of someone skilled in the art? That application doesn't seem to have published yet, so we'll see what they have at that point.
But let's wind up by emphasizing that "skilled in the art" point. As a chemist, you'd expect me to say this, but this whole problem was caused by a lack of input from a skilled medicinal chemist. El-Deiry's lab has plenty of expertise in cancer biology, but when it comes to chemistry, it looks like they just took what was on the label and ran with it. You never do that, though. You never, ever, advance a compound as a serious candidate without at least resynthesizing it, and you never patent a compound without making sure that you're patenting the right thing. What's more, the Oncoceutics patent estate in this area, unless I'm missing some applications that haven't published yet, looks very, very thin.
One compound? You find one compound that works and you figure that it's time to form a company and take it into clinical trials, because one compound equals one drug? I was very surprised, when I saw the patent, that there was no Markush structure and no mention of any analogs whatsoever. No medicinal chemist would look at a single hit out of the NCI collection and say "Well, we're done - let's patent that one single compound and go cure glioblastoma". And no competent medicinal chemist would look at that one hit and say "Yep, LC/MS matches what's on the label - time to declare it our development candidate". There was (to my eyes) a painfully inadequate chemistry follow-through on TCI10, and the price for that is now being paid. Big time.