DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
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Misassigned (top) and corrected (bottom) structures of bioactive TIC10.
PIC FROM
Don’t forget the chemistry
In a bit of a whoopsie it has come to light 1 that a compound TIC10, a stimulator of gene expression for TRAIL and in PhI/II clinical trials has in fact got an incorrect structure or rather the compound that was protected in the patent was assigned the incorrect structure. It was patented in a single compound patent 2 – which might ring alarm bells for some – were they really that confident they had the best compound. A quick look at the patent revealed large amounts of in vitro work but none in vivo again begging the question how good is this single compound. The compound had been identified by a group at Pennsylvania State University and licensed to Oncoceutics from screening of the NCI compound collection but the team, as reported, only attempted structural characterisation by MS. This would be unlikely to differentiate regioisomers which is what the problem turns out to be. It does however seem strange that the patenting error was not detected during resynthesis and scale-up for progression to the clinic. The error was picked up when a group from the Scripp’s 3 who synthesised the patented compound but found it inactive while they found the NCI batch to be active. They characterised the patented (inactive) and non-patented (active ex NCI) structures by crystallography and total synthesis. The corrected structure has now been patented by the Scripps group and licensed to Sorrento.
Of course this is all a bit embarrassing for those concerned but also more seriously could end up with extensive patent litigation, wasting money and discouraging investors from supporting the work until the patent situation is clarified causing delay in progressing the asset. Please please talk to medicinal chemsist early in a project this one looks like no one did which has led to an expensive mistake.
1. S. Borman Chem Eng News 2014, May 26 page 7
2. US Patent US8673923
3. N. T. Jacob et al Angew. Chemie. Int. Ed., Article first published online: 18 May 2014 DOI: 10.1002/anie.201402133
The fog is beginning to lift on how a mistake in the structural analysis of a promising drug candidate occurred and was sustained for so long that the agent was nearly in human clinical trials before the error was discovered.
Kim D. Janda and coworkers at Scripps Research Institute California recently discovered that the structure of a promising cancer drug candidate, called TIC10 or ONC201, had been misassigned in the agent’s patent (Angew. Chem. Int. Ed. 2014, DOI: 10.1002/anie.201402133). The biotech firm Oncoceutics, which has licensed the patent (U.S. 8673923), is sponsoring Phase I/II human clinical trials for the agent, which are currently in a prerecruitment phase. But Scripps has applied for a patent on the corrected structure and has licensed it exclusively to another company, Sorrento Therapeutics (C&EN, May 26, page 7).
TIC10 originated with a 1973 German patent (2150062) owned by C. H. Boehringer Sohn, in Ingelheim, now called Boehringer Ingelheim. The now-expired patent covers a family of 43 compounds, one of which is now called TIC10, and their possible use as antiseizure medications. It also contains a recipe for synthesizing the compounds.
At some point, the National Cancer Institute (NCI) picked up TIC10 for its publicly accessible Diversity Set II database, which researchers can screen freely to find agents with interesting activities. The compound’s structure shown in the database listing was the same as in the German patent—with three rings fused in a linear fashion.
Wafik S. El-Deiry of Pennsylvania State University and coworkers discovered that NCI’s TIC10 sample had potent anticancer activity (Sci. Transl. Med. 2013, DOI: 10.1126/scitranslmed.3004828). They used mass spectrometry to try to confirm that the structure of the compound was the same as that listed in the NCI database. But MS is inadequate for structure confirmation when used on its own.
Penn State was granted a patent to use TIC10 to treat cancer, and it licensed the patent to Oncoceutics for development. The company used the Boehringer recipe to develop a production process to produce sufficient amounts of the compound for study and eventually for clinical trials.
When Janda’s group decided to study TIC10 for possible use in a combination therapy, they opted to synthesize the three-ring linear structure from scratch, instead of using the Boehringer recipe. The compound they made that had that structure was bioinactive, so they ordered the compound from NCI and found that agent to be bioactive. When they then analyzed the bioactive agent carefully, they found it to have a structure in which one of the three fused rings is at an angle to the other two. They then synthesized this angular structure from scratch, applied for a patent on it, and relicensed it.
The reason the structural problem with TIC10 persisted so long is that until Janda’s group joined the TIC10 game, others all seemed to be using the Boehringer recipe to make it and were thus synthesizing a bioactive but structurally misidentified compound.
Oncoceutics Chief Business Officer Lee Schalop notes that all of the company’s research on ONC201, including studies required for approval of the agent’s Investigational New Drug Application with the Food & Drug Administration, were carried out with the bioactive agent. Oncoceutics did not reply by C&EN press time to an inquiry about what techniques it used to characterize ONC201 during its studies.
A number of reagent suppliers have also been marketing TIC10 for research purposes. A search of Chemical Abstracts Service databases in May showed that eight companies were selling CAS Registry Number 41276-02-2, the compound with the misassigned linear structure. (CAS is a unit of the American Chemical Society, which publishes C&EN.)
Sigma-Aldrich, one of the companies offering TIC10, hired a contractor to synthesize TIC10. But the company didn’t officially launch the compound for sale and didn’t ship any to customers. In response to the Janda publication, Sigma-Aldrich halted the product launch.
Sorrento patent attorney Jeff Oster tells C&EN that a meeting between Oncoceutics and Sorrento had been scheduled to begin untangling some of TIC10’s patent and licensing issues. But Schalop says Oncoceutics has no plans to meet with Sorrento.
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