Why did the company license the technology originally? Because c-Jun is a proto-oncogene that was suspected to be involved in cell proliferation, tumorigenesis, and the stress response. And so after JNK was first described definitively in 1993, the founders of the company saw it as an opportunity for therapeutic modulation.

"SP" stands for Signal Pharmaceuticals, and 600125 was just the compound number in our library. Nothing more.

As a drug discovery company we had set out to look for small molecule inhibitors of JNK. The reason this paper gets cited a lot, or at least one of them, is that this was the very first compound discovered that selectively blocks JNK, and not the other two kinases that are closely related and are frequently co-activated in the same disease models. Those two are p38 and ERK. There had been compounds that inhibited two or more of these kinases, but not JNK alone until our compound. Typically when people are studying inflammation, immune responses, cell proliferation, etc., all of these get activated. And so people could never really work out which of these kinases was responsible for the cell response they were studying. There was a selective inhibitor of p38 available, but really no such thing for JNK or ERK. Our compound could really discriminate between those three. And generally small molecular compounds are much easier to use than peptide- or nucleic acid-based inhibitors. It was originally manufactured in the 1950s as a dye-stuff, so it’s been out there a long time. What we did is identify it as a JNK inhibitor, and so we have a patent for its use as a JNK inhibitor.

It’s really both. JNK is a really hot area of research. This whole MAP kinase signal transduction is a big area of research, partly because it’s involved in so many of these cell processes. Then along comes this really handy-dandy reagent, which allows you to monitor and measure JNK involvement, so it’s going to get used a lot.

We don’t profit financially from this compound. For us, as drug people, it’s a proof-of-concept compound. It allows us to really ask the question of whether a small molecule inhibitor of JNK can be an effective therapy.

The answer is we believe absolutely that’s the case. People have used this compound now in many, many animal models of disease, and they’ve shown that it prevents disease progression or further injury. Our responsibility as a drug company is now to find a drug molecule that has all the physical chemistry properties you want in a drug and is safe for human use.

Many companies have gone after JNK. They’ve screened their libraries, had drug optimization programs. Some have been unsuccessful and stopped and moved onto other things. Others have been successful and are pushing on into the clinic.

Since then we have expanded our drug discovery program, and we have three compounds that are drug candidates. One is in the clinic right now; it has been tested on human subjects.

I can’t comment on that right now. I can say that it has completed a couple of phase I studies, which are safety studies. That compound number is CC-401, and we actually have two papers published on that compound, although we haven’t disclosed the structure. We are disclosing its efficacy and how it works.

I think maybe the easiest way to think about it is that JNK is an enzyme found to be highly activated at sites of injury. Therefore you can say that it’s associated with many pathologies or diseases. What we have to do is unravel how causative it is for each of these diseases. So the analogy is that if there’s an incident somewhere and you rush to the scene and find 200 people hanging around, you still have to figure out which one of those 200 people were responsible for it, and which are just bystanders.

I guess definitively it’s when a targeted drug prevents disease. At first you test models of the disease pathology you’re interested in—these can be cell models, animal models, ultimately human clinical trials themselves—with many types of JNK inhibitors. If your compound attains the end point of the study, which is usually going to be a marker of disease or a symptom of disease, then the conclusion is that JNK is driving or causative of that pathology.

I can tell you the story very quickly. We had a screen. We basically had the enzyme and substrate in high-throughput screening plates. We rationally went after compounds that would block the activity of this enzyme. So none of that was serendipity. We got a large number of hits and we sifted through them, which is what you do in this process. "We" means myself and a colleague who is now at Pfizer, Brion Murray, and the chemist who was assigned to this project, Yoshi Satoh. And so we looked at this molecule and said, "What can we do with this?" We had the activity, and that was quite potent, but the structure was not attractive. We each did a number of things, and a key one was to put it in a number of cellular assays, and we found that it behaved just as you would hypothesize a JNK inhibitor would behave. So it blocked the phosphorylation of AP-1, the expression of AP-1 regulated genes, and it did in a dose-dependent manner. This was a good starting point, a proof-of-concept compound that we could use to probe whether JNK is really going to be a drug target or not, whether small molecules that inhibit JNK will behave as a drug. It was a new platform from which we could jump, a really big stepping stone. We had a tool, and we could really go through cell systems and animal models and hypothesize much better what role JNK is playing in disease.

We probably first picked up the compound in 1998, and the paper finally appeared in November 2001.

In fact, it was more a case of finishing the experiments and sitting down to write up the paper. I probably submitted the paper in late 2000. Then it was reviewed. We made changes, etc. We were happy to publish because we didn’t have the composition-of-matter patent on the structure. It was a known compound. It’s just that no one knew it was a JNK inhibitor. One thing that comes out of this is that we learned a lot by getting our tools out to the public and letting the research community, unknowingly, do our research for us. This is really beneficial. We have strategic collaborations, in which we actually hook up with people who have a specific model or research of interest to us, but as a program we have learned an enormous amount by reading papers on research that we never knew was coming. The weight of all that research has been useful to our program to push it forward. It’s a bit like those advertisements that tell you to use the power of the internet to make decisions for you. Here you put a tool out there and everyone takes it up and uses it and publishes their data. I could say that I have, indirectly, several hundred people out there working for me.

In hindsight, no. But I knew people would want this compound. There was no question about that. What I didn’t know was how many people were working in this area. As soon as we published, we got inundated with requests for the compound.