Evolve your Compound
No drug will ever get to the market alone. Watch as our chemists, biologists, and pharmaceutical scientists - who share a hallway at our UK site - discuss their integrated approach to design, synthesize, and optimize compounds to evolve your compound for therapeutic use. Our team asks the right questions to get you the answers to move forward.
Omar Aziz (00:15): The main idea is we build better molecules. And molecules that are more efficacious, that are more stable, that actually have greater access to target tissues and organs. So each time we go through these cycles of building better molecules, it pings between all three groups. And it's just about driving to get the best molecule. Russell Scammell (00:43): Hi, my name is Russell Scammell. I'm director of chemistry and analytics, and I am mainly responsible for the pharmaceutics group. This line of work for me is just so interesting and there's so much opportunity. Every day is different. We work with some fantastic clients. They usually come to us with a range of problems that they want us to solve, so every day is different. So that's why I love coming to work every day. Karen Williams (01:08): I've always been interested in science from a very, very early age all through my schooling and chemistry just caught my attention. The ability to make compounds from rudimentary building blocks, and then to use that for drug discovery was always something I really wanted to do. Omar Aziz (01:26): I can see the impact that we make. I'm aware of how many different sorts of diseases become more and more aware of and the impact of that on cultures just seems to be getting bigger and bigger every year. And I think anything we can do to mitigate that and to improve the quality of lives of people has got to be worthwhile investing time and energy into. Karen Williams (01:48): It is a proper team effort. No drug will ever get to the market with one individual working on it. So every team is equal in the process. And as Omar said, you do have to have some fun. Science is notoriously full of negative feedback. That's the nature of science. But actually that's what drives people forward is to actually then get something that works. It may be one in a hundred compounds, but that's the dream is to get something that moves forward. Omar Aziz (02:29): I always joke about chemists being the most optimistic people in the world. Because it doesn't matter how many compounds they've made but just have not met the grade, they're still excited about the next one. Russell Scammell (02:39): I think the drug discovery process is a little bit of an unknown quantity. For most people, they see the final product but they don't necessarily understand how we've achieved it. And I think it's just really interesting for them to understand and talk to me about it. Karen Williams (02:54): My role is that I will manage the chemistry teams associated integrated projects. And what we will do is we will design the compounds to begin with, then we will find what the synthetic route is in order to make the compound. Once the compounds are made, then they will be purified and then they'll go off to Russ's team. And in Russ's team, he will do the QC, they also do some final purification of compounds that going into screen. Russell Scammell (03:24): So the compound could come to us in a variety of different ways. We work really closely with our chemistry teams here. So the compound can come straight from chemistry. I'm responsible for the scale-up chemistry team as well. And we work closely with those chemists to actually analyze that material, to make sure it's the correct polymorphic form that it's stable, that it's pure, et cetera. Omar Aziz (03:47): So what do we do with the compound? Lots of compounds. So we get lots of compounds coming to us for testing. So we determine how efficacious it is at target. So we set up biochemical assays which look at a really clean system so our chemists can understand what's going on from a binding perspective, how strongly does it bind? Does it bind quickly or slowly? We then progress those compounds that are potent enough to more complex system, so cellular systems. So we're then looking at how they behave, where there's a lipid barrier to getting into a cell, where there's loads of other proteins that the compounds can interact with. Is it still binding to target? Is it massively shifted from what we see biochemically? So we're there to determine is, how does it bind on its own and in a clean environment? And can it do that reliably on a cellular basis? Omar Aziz (04:39): The process always starts with target validation. I think regardless of the stage clients we're working with or any drug discovery companies we're working with, they need to be absolutely certain that that target they're looking at is relevant to the disease, is relevant to patients. And it's relevant to the model systems we're actually working with from an in vivo perspective. So from a biology side, our aim is to build assays that specifically target that, and really get down to the nitty gritty of what can you resolve from it on a biochemical basis? What can you resolve from it from a cellular basis? And are there any markers of engaging that target that we can start looking at early that will translate later on in the process? Karen Williams (05:18): So from a chemistry perspective, the idea is to take the information from the target validation, knowing it's a real valid target with a disease indication we want to work on and try to find some chemical matter to work on. So there are a variety of different tools we can use to find that chemical material. And then we take that from the very early stages of identifying it, progressing it through the drug discovery process. So that's through a hit ID phase, hit-to-lead, into lead optimization, all the way through to pre-clinical candidate nomination. Through that process, the compound's progressed to a screening cascade. It's a team effort in order to make the compounds, in order to test them through the biology screens, to test them through the [ATMI 00:06:03] screens. And then for the analytical team to do the QC, the analysis, to find that you're making the right compounds and then to formulate them to go into the in vivo studies. Russell Scammell (06:14): So from pharmaceutics, we like to get involved as early as possible at the end of lead optimization. We really look at the compounds and triage as early as possible, and that triaging could be based on stability or solubility or formulation characteristics. From that point on, we look at detailed pharmaceutics analysis, so polymorphism, salt selection just to really de-risk compounds as early as possible within the process. And then again, we'd like to get involved as a later stage, looking at formulation characteristics for PK studies, et cetera. Omar Aziz (06:50): So the benefits of having us collaborate on projects is decision-making. The understanding where all those aspects are coming in from and what the considerations are and faster turnaround times. And you want a tight knit group so you can get [inaudible 00:07:05] rounds of testing done. You want to know as soon as possible, whether something's working or not. And if you can limit those gaps between, you make better decisions faster. Russell Scammell (07:14): The work dynamic is fantastic here. Again, it's the opportunity to get involved with so many different aspects of the drug discovery process that just weren't available in other areas that I've worked for. It's a collaboration on a day-to-day basis. Karen Williams (07:27): I guess you can work with any CRO and the CRO can just execute the piece of work that you've asked them to do. The difference with Charles River is that we can work collaboratively with those clients and deliver at the project level. So we take it for granted that we'll carry out the science. We have an amazing team of exceptional scientists, but I think until you bring that together in some collaborative way to achieve a team goal, then that's how we add that value for our clients. And hopefully that's what they see from working with Charles River. Omar Aziz (08:00): It's good fun. It is good fun. I think one of the big side of it is you have to have a sense of humor going through the challenges. Because quite often, let me say, it's the stuff that you don't see coming that blindside you. Karen Williams (08:10): Yeah. Omar Aziz (08:12): And in a way that's nice because no two programs are ever exactly the same. There's always going to be some aspects that differ even just under the chemical series on a similar target, you can find differences that are there. So we're constantly learning. And I think that's probably what makes it so much fun is that no one starts off knowing it all. And even people who've been in the industry 20, 30 years, they learn new stuff every day as well. Karen Williams (08:35): So failure is actually a really strong thing to reward people for doing. So fail fast and fail early is much, much easier than taking something through to the clinic. Clinical trials become really expensive. So it's really, really useful if we can kill compounds or kill projects early. Nobody likes doing that but it is just a fact of science that not everything, not every project, not every biological target we look at, not every one of them can be a druggable target with ... Can be successful in the clinic. Russell Scammell (09:09): The end result is a drug that's in the market that is hitting the target and can be used on a day-to-day basis across a range of activities. Karen Williams (09:20): Well, we're always happy when we see them move on. So you don't lose contact with the compounds. So even though they move on to a different part of the drug discovery process, we still get feedback and communications of how they're progressing. And the ultimate goal of course, is to get a drug that you've worked on as a team through to a marketed drug which can treat human patients.
“From a chemistry perspective, the idea is to take the information from target validation, knowing it's a real valid target with a disease indication we want to work on, and trying to find some chemical matter to work on. We will create the compounds on paper and then… synthetically deliver those compounds by making them in the lab. The design of the molecules is… the most important piece. Of course, making the compounds is really important, but understanding the data that comes out of those screens and making the next iteration of compounds is the challenging piece for most projects.”
-Dr. Karen Williams, Director of Operations
“The process always starts with target validation. Regardless of the stage, clients we work with need to be absolutely certain the target we’re looking at is relevant to the disease, patients, and model systems we're actually working with from an in vivo perspective. From a biology perspective, our aim is to build assays that, specifically, target that model, and then we ask: what can you resolve from a biochemical basis? What can you resolve from a cellular basis? Are there any markers of engaging that target we can start looking at early that will translate later on in the process?”
-Dr. Omar Aziz, Senior Director, Biology
“Pharmaceutical scientists like to get involved as early as possible in the drug discovery process. We look to actively triage compounds based on stability, solubility or formulation characteristics. From that point on we look at more complex areas of pharmaceutical analysis such as polymorphism and salt selection, our primary aim is to de-risk compounds within the discovery process. We also ensure we have involvement at a later stage looking at advanced formulation characteristics.”
-Russell Scammell, Director of Chemistry and Analytics