The Synthesis of an Entrepreneur: Merging a Passion for Biochemistry, Synthetic Chemistry, and Bioactive Molecules in Academia

INNOVATION THAT MATTERS

By Rich Soll, Senior Advisor, Strategic Initiatives at WuXi AppTec (@richsollwx)

Synthetic chemist Joseph Ready believes a huge amount of innovation in the drug industry comes from academia. Academic science is arguably the greatest source of innovation in our ecosystem, yet faces challenges when considering the transition from the lab to early stage company formation.

Ready – who holds a Bonnie Bell Harding Professorship in biochemistry and is a Southwestern Medical Foundation Scholar in Biomedical Research UT Southwestern Medical Center – has been successful at translating his science into early-stage commercial ventures. His work has led to the development of at least two start-ups: Proneurotech, which he founded with Dr. Steven McKnight of UT Southwestern, Dr. Andrew Pieper of Case Western University, and Marc Freeman of Oregon Health Sciences, is focused on discovering and developing neuroprotective drugs that prevent axon loss after acute injury or chronic degenerative disease. Rodeo Therapeutics was co-founded with renowned cancer researcher and medical oncologist Dr. Sandy Markowitz and Dr. Stanton Gerson, also a researcher at Case Western University.

Meanwhile, The Ready Lab is engaged in the discovery and synthesis of biologically active small molecules. The lab focuses equally on natural products and synthetic compounds emerging from high-throughput screening efforts. Ready and his team of researchers collaborate with biologists at UT Southwestern, and elsewhere, to discover small molecules with promising biological activity using high-throughput screening strategies. They are also involved in efforts to identify small molecules with relevance to neurodegenerative diseases, cancer, and infectious disease.

The lab’s current research is directed toward the discovery of novel cycloadditions and catalytic C-C cross-coupling reaction. Ready and his team anticipate that the combination of these efforts will greatly expand the power of organic chemistry and enable the rapid and efficient synthesis of valuable complex molecules.

I recently spoke to Ready, who shared his insights on the thrill of discovering new chemistry and the merging of scientific research with entrepreneurialism.

Rich Soll: The first thing I want to do is talk about your medicinal chemistry lab at UT Southwestern. Can you provide us with some background?

Joseph Ready: The medicinal chemistry lab grew out of a program project grant that was centered in the Department of Biochemistry. It was headed by Steve McKnight, one of the founders of Tularik who then moved to UT Southwestern in maybe ’95 or so. One of his main objectives was to integrate medicinal chemistry and synthetic chemistry into the Biochemistry Department, so he launched this initiative to bring in synthetic chemistry groups – mine, Jef De Brabander, Patrick Harran, and Chuo Chen amongst others. At the same time, he was great at orchestrating collaborative research among various groups, so he put together this program project grant focused on chemistry and cancer. He built a high throughput screening facility that’s headed by Bruce Posner, a former Pfizer scientist. We have a small molecule preclinical pharmacology group that does in vitro ADME work and some rodent work, and then the third leg of that stool was the synthetic chemistry facility.

Over last 10 or 15 years I’ve taken over as the director, it has grown both in terms of the funding streams to have some support institutionally as well as grant support for a variety of projects. We work closely with the high throughput screening and the preclinical pharmacology groups. The basic outline of projects is that investigators from across the university discover a protein of interest or develop an assay that they’re interested in screening for small molecules; they work with the HTS group to put a screen together and then after that is done we get involved. We work with many other groups on the biology side and some of those are sort of cursory: giving guidance on what things to buy, which compounds are attractive and which aren’t. And then some of them are full-fledged medicinal chemistry efforts trying to optimize compounds and anywhere in between.

Rich Soll: What would be the end game in those kinds of scenarios when we talk about optimization?

Joseph Ready: The way I envision our role in academia is basically target validation. What we want to be able to do is work with biologists to find a new target and show that that has some therapeutic benefit in an experimental model. It’s unlikely that we’re going to make the final clinical candidates, but many of the steps that we need to take along that optimization process are useful for tool compounds as well as for finding the ultimate clinical compound. So, we’re trying to address potency and solubility and PK properties and toxicity, all of these types of things basically to get a compound that works in a mouse or a rat.

I think that’s probably the kind of the end of the road for what we can really do in an academic setting is to try to get some evidence that we can engage a target in vivo and that it has a therapeutic benefit. That’s the most exciting obviously when we have a new target because, because it sort of opens up the doors for either a small company to take over or bigger companies to become involved.

Rich Soll: What led you to co-found Rodeo with Sandy Markowitz and Stan Gerson at Case Western?

Joseph Ready: It was matchmaking by Jim Willson, who now the scientific director at the Cancer Prevention Research Institute (CPRIT) at UT Southwestern,  He was head of the Case Western Cancer Center and then UT Southwestern recruited him about six years ago to take over the cancer center here.  His charge was to turn us into an NCI Comprehensive Cancer Center. He had been a longtime collaborator with Sandy, and both of them are medical oncologists interested in colorectal cancer. And I think Jim basically was making cell lines and Sandy was doing genetics on those cell lines. There was not a high throughput screening facility at Case. But there was one at UT Southwestern, so Sandy ran the screen to find modulators PGDH here. That’s when we got engaged essentially.

Rich Soll: What drew you to form Rodeo with Accelerator Life Science Partners?

Joseph Ready: We had found compounds that worked well enough, and we could take them into a mouse, they were chemically stable, they could engage the target, and they had a therapeutic effect in three or four different animal models of disease. It was clear that we needed expertise and resources beyond what we had to push these things forward. We lack the experience to design those studies and to really interpret the data.

I think once we really had compelling evidence of compounds working in animals, we started looking for ways to move this into a commercial venture. And the specific connection to Rodeo came through one of the strategic partners, J&J.

Sandy knew some people there and those people put us in touch with the Accelerator Life Science Partners team and we pitched it and kind of went back and forth through their due diligence and due diligence on our side trying to understand their business model.

Rich Soll: So, it was through a personal connection of Sandy’s?

Joseph Ready: Yes, it has been my experience that it is a personal relationship between some scientist and a venture capital person or a scientist and somebody at a company.

Rich Soll: I know Rodeo is in the early stages, but can you give any updates?

Joseph Ready: It is still in the early stages and we’re continuing to show interest in inflammatory bowel disease and recovery from bone marrow transplantation and other areas of tissue regeneration.

Rich Soll: Can you briefly describe the papers you and your colleagues have published?

Joseph Ready: The program has published three papers – a Science paper that provided the initial reports of the biology; then we had a J. Med. Chem. paper showing our work to develop some more soluble compounds, and that was really the objective because we were targeting bone marrow transplantation that requires I.V. in a human.  There was third follow-on paper with Sandy and Stan in Hemotologica that used one of the optimized compounds from the MedChem paper.

Rich Soll: Can you summarize some of the key findings in the paper?

Joseph Ready: In the MedChem paper, we had the great luxury of the early compounds solving our potency problems. I think the key findings of the Hemotologica study were that the compound is active in combination with GCSF, and we took that as an important bit of information because any early clinical trial would have to be in patients also receiving GCSF. Both of those agents double neutrophil levels. Then when you use both of them you get a further doubling. So, there is at least an additive effect of our compound on top of the current standard of care. That was point number one.

Point number two was it didn’t matter how many cells you gave in the transplant, the drug always had an effect. So, if you get a low amount of cells, we increase to a high amount of cells. We still think we increased it even faster. We don’t saturate the response by just adding more cells – whatever the transplant is we always increase the pace at which it reconstitutes the neutrophils red blood cells.

The third point was you can do this in old mice. That’s relevant because many human patients are not young when they’re getting bone marrow transplants. They did aged mice, and again we saw the same beneficial effects of drugs. I think those were the kind of the three punchlines in the study, which were really terrific.

Rich Soll: Very nice. This work is certainly illustrative of some of the great biomedical research in Texas. Is there a focus or uniqueness to the biomedical research that’s conducted at UT Southwestern?

Joseph Ready: I think there is maybe a bias towards cancer because there is a National Cancer Institute and there’s CPRIT so there is an availability of funding associated with cancer that is not matched in other areas,

Beyond cancer, the chairman of our department has a Phase 3 candidate for malaria for example; one of the projects that we’re excited about is targeting leishmaniasis.  There’s a lot of biology first discovered in Texas beyond cancer, for example HMG Co-A reductase, the target of statins.

Rich Soll: For your research, you’re doing oncology, but you also have an emphasis in regenerative medicine and neuro degeneration. Can you give me a sense of what’s come out of that, because you’ve done several deals already, and some of your stuff has been licensed outright?

Joseph Ready: Yes, that’s right. We teamed up with The Column Group, a VC based in the Bay Area, and we started a company called Proneurotech that is in the neuroscience area. That’s been a long-standing collaboration, probably a decade, with Steve McKnight and Andrew Pieper. Steve was the chair of biochemistry at UT Southwestern recently; Andrew just moved to Case Western.

Rich Soll: Going beyond your group, can describe some of the entrepreneurial spirit at Southwestern?

Joseph Ready: There’s a good amount of it. Right next door is one of my chemistry colleagues Jef De Brabander who been involved in starting maybe three companies including Reata; one of our other colleagues just down the hall started a company. At this point, I’d say within the biochemistry department, maybe half of the department is one way or the other involved in some sort of company.  There’s a pretty high percentage.

Rich Soll: Do the companies tend to be local or do they migrate out to the centers?

Joseph Ready: I would say all of the above. Jef’s company is called Reata Pharmaceuticals, which is based in Irving, Texas. They have a number of Phase 2 trials going on.

Our neuroscience company is in the Bay Area. There’s another company Peloton, which is local. We had some early involvement in that; several other members of the department are more involved in that company. They have clinical trials going on targeting hypoxia inducible factor 2.

Rich Soll:  Where do your compounds come from?  Do you have a screening deck?

Joseph Ready:  We have a screening deck of 350,000 compounds, 90% commercial from library vendors.

Rich Soll: In your view, how successful is academic drug discovery? It sounds like UT Southwestern is ahead of the curve a little bit in terms of percentages but maybe you could talk a little bit more about that.

Joseph Ready: I think if the question is, are drugs coming directly out of academia? I think there are very few. There certainly are some examples. There’s a drug from UCLA on pancreatic cancer and there are very successful antivirals from Emory, and some pain medications from Northwestern, and AIDS drugs from Princeton. So they certainly exist, but those are the exceptions rather than the rule. If an academic lab makes a molecule and that molecule ends up being in a bottle in the pharmacy, that’s very uncommon.

But I think a huge amount of the innovation in the drug industry is starting in academia, and then moves to biotech. If they’re successful, biotech gets licensed by big pharma. That seems to be the model to me as big pharma has evolved into a drug development organization whereas the early innovation is derived from academics because that’s where the new biology is coming from.

Rich Soll: What are some of the challenges that you generally face though as you move your own research or research interest through this kind of  paradigm?

Joseph Ready: Although funding is certainly problematic and I think the difficulty with the early stages of projects is two fold:  (1) funding of speculative research is not encouraged, and (2) criticism before a project is funded that says, “well this isn’t going to work;” “nobody’s ever done this before,” or “it’s highly innovative but low probability of success” followed by criticism after you show success that says  “well it already works, where’s the innovation?” There’s little incentive to follow-up on the “unexpected.”

Rich Soll: How important are CROs in helping to support academic research?

Joseph Ready: WuXi has enabled our research in several ways.  Prior to Rodeo, we used some of WuXi’s synthesis capabilities to scale up compounds for POC studies in animal models.  We are also working with a team outside of Rodeo on analog synthesis. The WuXi team has been great – very high quality, very responsive, and overall a good organization. Tracking the data that is generated can be challenge, but WuXi has been very helpful in tracking everything.

Rich Soll: What is your inspiration every day?

Joseph Ready: I think it’s the excitement of problem solving. It really is just the science of understanding biological systems and trying to make compounds that have a specific function.  Obviously, the therapeutic impacts that we could envision down the road are great, but on a day-to-day level, it’s the thrill of discovering new chemistry or putting molecules together in an interesting way or finding a compound with an improved signal or profile or whatever it is. It’s really the mechanics of solving specific problems and understanding how the chemistry affects the biology.