June 19, 2013
"I recall early on trying to understand what should I do if I’m interested in science, but I’m not interested in medicine so to speak, like, being a medical doctor. And I was reading some descriptions about pharmacology and then I realized that sounded pretty exciting and also fit what I really thought I would like to do. That took me to pharmacy school. And in pharmacy school, I really realized I was more interested in the research and so I went the research path... That was over 20 years ago. And between then and now... NeurOp was really what I always wanted to do. I think this level of the in-vitro pharmacology and evaluating novel molecules has always been my main interest."
Scott Myers, Ph.D
Director of Drug Discovery
NeurOp
Scott Myers joined NeurOp as its director of drug discovery in 2006. He has helped lead efforts to develop subunit-selective NMDA receptor antagonists, from discovery through lead optimization, as potential clinical candidates for the treatment of cerebral ischemia, including subarachnoid hemorrhage, pain, and depression. Dr. Myers trained in the laboratory of Dr. Ray Dingledine and collaborated with Dr. Stephen Traynelis on the evaluation of NR2B-selective antagonists. He received his Ph.D. in pharmacology from the University of North Carolina at Chapel Hill.
Interviewed by Barry Bunin, CEO Collaborative Drug Discovery, Inc.
Listen to the Full Audio
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Edited Interview Transcript
Barry Bunin
I appreciate your doing the CDD Spotlight. I wanted to start with some basic neurobiology, if you will, and just explain a little bit about the glutamate receptors in general and the NMDA receptors more specifically.
Scott Myers
The glutamate receptor class is a class of excitatory amino acid neurotransmitter receptors. They are very prevalent in brain; practically every neuron has a glutamate receptor. And they come in three main varieties. There are AMPA receptors, kainate receptors, and NMDA receptors, named after selective agonists, pharmacology going back into the 80s. The NMDA class is best known as a coincidence detector that is critical for establishing long-term potentiation (LTP) at synapses which is a molecular correlate of learning and memory. The NMDA receptor is a calcium ion channel and it’s blocked by magnesium in a voltage-dependent manner. And this receptor comes in four main subtypes defined by the NR2 subunits and it turns out that they are very interesting receptors for a number of neurobiological events - learning and memory, development, things of that nature. And when they go wrong or they’re not functioning properly, folks may suffer schizophrenia-like symptoms, or during periods of stroke, over-activation can lead to cell damage and cell death. So it’s been a major interest in pharmacology and drug development for several decades now.
Barry Bunin
So for complicated diseases like schizophrenia that involve things like our consciousness and the essential aspects of one’s self, how has the literature emerged to understand in a reductionist or mechanistic way the CNS biology around these very complicated events and diseases?
Scott Myers
The concept of how the glutamate system is involved in schizophrenia really stems from findings going back many decades where folks were taking substance abuse compounds such as phencyclidine and Ketamine. These compounds are channel blockers of the NMDA receptor. They’re more or less nonselective for the subtypes that I mentioned. And it turns out that when folks take these substances, they display symptoms and psychoactive affects that are very reminiscence of what schizophrenic patients experience. And so this concept of a reduced function or hypofunction of NMDA receptors emerged, and that really stems from the clinical findings of these compounds. Since then, there have been a few animal models where they’ve tried to knock down subtypes of the NMDA receptor in certain neurons and these mice display behaviors that are again symptomatic or reminiscent of what we think a mouse might undergo if they’re showing symptoms of schizophrenia. So it’s really out of some of the pharmacological tools that emerged several decades ago that have led today to our interest in trying to develop compounds that might be useful to treat this disease.
Barry Bunin
Given some of the recent, CNS advances in the news, there was some news out of Stanford about a new way of visualizing transparent brains by replacing the brain’s lipids with a hydrogel around the neurons and there’s the Nobel Prize for GPCR research recently and a greater appreciation of polypharmacology in gene families like GPCRs and kinases, and I was just wondering how the evolution of our understanding of the brain and CNS drug discovery has been developing within your field? Can you share areas that you’ve seen either of interest directly to your field or developing in parallel with your field to share some interesting advances.
Scott Myers
One of the areas we’re focused on, and we’re not the inventors of these concepts these have been around for a long time, but the interplay between different types of neurons and circuits have major impacts on cognition and learning and memory as you might expect. So I think the sort of studies that you’re referring to are very important in really understanding the interplay between inhibitory neurons and excitatory principal cells between different regions of the brain. And that’s the idea that we and others have around modulating the NMDA receptor subtype in subunit selective ways to modulate specific sets of neuronal populations as critical control points regulating circuit physiology, and then ultimately the behavior of a person. So those concepts I think are very important and as we move into the future I think they will become increasingly important.
Barry Bunin
Let’s talk directly about the work you do at NeurOp. Since we talk at Collaborative Drug Discovery about collaborations, can you share a bit about the work you do at NeurOp and the work done at Emory and how those two complement each other? Which place is best for doing which type of work and how that has evolved over the years?
Scott Myers
NeurOp was founded around 2002 and we really got our feet off the ground in 2006. The discoveries that are the founding basis of the company were identified at Emory. That’s probably no surprise if you know anything about NeurOp. I’ll give you a little history as it goes back to how to protect nerve cells from dying following ischemic episodes such as stroke or heart attack. So the discovery efforts that go on at Emory are very fundamental, mechanistic-based discoveries identifying new concepts and new ways to understand a disease process by digging really deep into the mechanism of how the damage occurs. The concept is that the NMDA receptor is sensitive to protons, and therefore is inhibited when the pH levels in brain tissue decreases. It was combined with some early studies around the mechanism of action of CP-101,606, which is a well-known NR2B selective antagonist. And through the founding work at Emory, it was discovered that some of these NR2B selective antagonists actually are pH-sensitive in their ability to block the receptor. And combining that finding with the understanding of what happens when folks experience a stroke and pH drops, the idea is that one might be able to selectively prevent the cell death that occurs in that tissue bed in a very selective manner, and in a time dependent matter. Coming back to NeurOp, how to translate that finding into a clinical candidate really is the job of NeurOp. That’s what we’ve been doing in earnest since 2002, and we were able to develop a number of molecules with this property. So I guess in contrasting the two, we are a discovery-based company, and we still have strong ties to academic collaborators, but we’re also really extending those into clinical candidates as a real therapy to help patient populations.
Barry Bunin
Thanks, that’s wonderful context. I want to ask how do you use the CDD Vault and why have you decided to use the CDD Vault technology?
Scott Myers
Well, as we’ve grown as an organization and as our data sets have become more diverse and complex with molecules, data behind the molecules, and in the number of people we engage with, we understand the need to organize that data in a way that’s readily understandable by everyone across the organization, including our collaborators outside of NeurOp. So it’s been a very effective tool for us to manage our data set and help us understand the SAR of our molecules. And it was really good for us, because we’re not a large organization where we can really reach out and hire folks to build one on our own, and so it was a perfect fit for us. It allows us to accomplish the goals that we need without having to invest a significant amount of resources in building that from the ground up.
Barry Bunin
What do you personally like most about using the CDD Vault?
Scott Myers
I think it’s really the ready access to specific data. When I need to know it in the moment, you know, during a conversation or a teleconference, I know that the data is there and if I have my queries, some practice with that, I can retrieve that data in pretty much a moments notice, and that’s very effective when we need to answer questions on the fly or understand how to drive a chemistry decision based upon data.
Barry Bunin
You mentioned some collaborations and that the company was founded in Emory. Maybe just talk about the different types of work you do with collaborators whether Emory faculty or students or CROs, et cetera, just to get a sense of how the outside work compliments the internal work….and how that changes over time as the company grows. There are things that companies are very good at turning the crank on, and other things which they use externally.
Scott Myers
Right. So initially as we exited Emory and became NeurOp, the collaboration was more at the level of the intellectual side through the founders and their directions of the company’s research. Since then, we’ve been able to write grants to the NIH and in those applications and in the work that we do, we have been able to support our focus on the in vitro properties of molecules and how they engage the NMDA receptor. We also have chemistry, so we have a pretty strong understanding and experience around making the proprietary molecules and evaluating them at their receptor. But internally we don’t have a large infrastructure where we can translate that through a lot of the lead profiling studies that are necessary for drug development, e.g., pharmacokinetic studies, metabolism, and many in vivo studies for side effects and efficacy. So our collaborations, many of them are with CROs to get data along preclinical ADME lines of study. And we also have some academic collaborators that we reach out to for expertise in certain in vivo studies where they have the experience and the understanding and frankly the equipment and the personnel to do those studies for us. And we found that it’s a good fit for us in today’s world. Building up large companies is a big challenge in today’s economy. And we find that this helps us use what we’re good at doing, by collaborating with what others are good at doing as well.
Barry Bunin
So today you’re the Director of Drug Discovery at NeurOp. And often times there are one or two formative experiences early on in one’s career that gets them excited to go the extra mile to really learn science and become successful, so maybe you could just talk about earlier in your career one or two formative experiences that helped intrigue you or motivate you to get to the point where you are today.
Scott Myers
That’s a good question. I guess I would describe my route to here as a very long and winding process, so to speak. I recall early on trying to understand what should I do if I’m interested in science, but I’m not interested in medicine so to speak, like, being a medical doctor. And I was reading some descriptions about pharmacology and then I realized that sounded pretty exciting and also fit what I really thought I would like to do. That took me to pharmacy school. And in pharmacy school, I really realized I was more interested in the research and so I went the research path. And then when I went to grad school in my research lab, I was really interested in the molecular pharmacology of receptors and I initially was interested in GCPRs largely because that was what my exposure was. I was able to get some experience in a lab that worked on glutamate receptors, at the time when the receptors were initially being cloned, and could do pharmacology on a specific subtype in a Xenopus oocyte, and that was quite novel at the time and this really got me excited about the discovery aspect and the interaction of drugs with receptors. That was over 20 years ago. And between then and now ( when I got this job at NeurOp) NeurOp was really what I always wanted to do. I think this level of the in vitro pharmacology and evaluating novel molecules has always been my main interest. And so it just took awhile to get there, so I guess that formative experience was in grad school. I went to a lecture around antibiotics and I remember coming back to the lab thinking: I just heard this lecture about this analog of glycine and I thought that might be operative or might work at the NMDA receptor. And so in that moment, I really thought that was something I wanted to do, SAR.
Barry Bunin
So in addition to the work at UNC, can you talk about how the work at University of Washington or Gladstone, complimented your perspectives. And maybe some of the other work is relevant, maybe it’s not, but just talk a little bit about some of the other things you’ve done.
Scott Myers
Well, the work at UNC I pretty much explained and the work at the Gladstone was interesting because it was an example. I was working there as a technician and it was a small lab - essentially, the goals of that project were almost identical to the goals of my work at UNC Chapel Hill and that was about cloning receptors and studying their properties in oocytes. I think the biggest value of that experience was in that we were successful in cloning that receptor and so that really consolidated some of that early interest and excitement I had around in-vitro evaluation and molecular pharmacology. My work as a postdoc at the University of Washington was instrumental. I got out of the glutamate field for a while. And it was still cell biology and biochem related, but it was focused on calcium channels. And that was just able to broaden my understating of classes of ion channels beyond the ligand-gated ion channels. But I realized I was a little more interested in the neurotransmitter receptors per se than voltage-gated ion channels.
Barry Bunin
Can you give a little bit of a sense of the other members of your team there, anything interesting or noteworthy in any of their backgrounds? Obviously you can’t go into details about everybody but just one or two interesting things, experiences that they bring to the team. If you want, you can remain anonymous to protect the innocence so to speak, but just giving a sense as to some of the interesting things that other people have done, even if you don’t name their names sort of gets a sense of how a team comes together and how their different backgrounds can synergize.
Scott Myers
Right. Right. So the founders of NeurOp, I think it’d have to start with the founders, I think we have a very strong pharmacology group, Ray Dingledine, Steve Traynelis, are both well-renowned scientists in the glutamate field and they're excellent pharmacologists, and Steve is an excellent molecular pharmacologist. We also have Jim McNamara on our board, Jim has a great deal of experience in neurology and understands CNS systems very well. So the company really started with a core of topnotch scientists and early on Dennis Liotta, a chemist at Emory who has significant achievements himself, and most folks don’t even have to be introduced to him, they understand what he’s done in the field of chemistry and antivirals. So that group as a core in founding the company has been very inspirational, I think, to the NeurOp team itself. Since then we’ve added internal chemistry. We’ve had some chemists that have come to us from pharma and also from biotech, and they have been very great in how they apply their experiences to synthesizing the molecules. Our CEO comes with a great deal of experience, Barney Koszalka out of Burroughs Wellcome, GlaxoSmithKline, and so he has a great deal of experience on really understanding how to translate preclinical molecules into clinical drugs. And recently we’ve been able to acquire the services of Rob Zaczek, and he comes to us from Bristol-Myers Squibb. So again, we have a great deal of experience there in understanding how to, again, take preclinical molecules into the clinic with the important understanding of how to do this in a CNS realm. And he’s also a great deal of experience in area of schizophrenia as well as other CNS diseases. So I think as a team now, we have a critical mass, and we have been able to get the right people in the right places. And I believe we are at the beginning of an emerging area of NMDA receptors and drug discovery, and we’re in a good position to take advantage of the skill set that we have to address the opportunities ahead of us.
Barry Bunin
Excellent. One of my last questions here is sort of a before and after. So before you used CDD, how did you manage your data or collaborate. And after, how is it better? And that can be a function of the technology, could be a function of interactions with the people at CDD or both, but just give us a sense of the additional efficiency or “the delta”, the change, before having implemented and after.
Scott Myers
Yeah, that’s another good question. Before CDD, we were an Excel spreadsheet-based organization, that’s where we have our data and pretty much I managed that. And the limitations, as I’m sure you’re aware of, is it’s sometimes very difficult to navigate and identify the data quickly. You essentially need to remember where those files are stored. As far as the delta after, I don’t think we actually know how big that delta is yet. We’re still fairly new to CDD, but what I know already is that across the organization everybody now is familiar and has access to the same data at the same time. And there’s no events anymore where folks say, "I don’t know where that data is," so to speak. So it’s really helped us with the efficiency of communicating and getting the important facts across the organization to the right people when they need it. And like I said, I don’t really think we’ve fully taken advantage of the delta yet, but it will be enormous. So we’re actually really happy that we have the CDD Vault.
Barry Bunin
That’s a perfect note to end interview on.
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