Evolution of a Compound (Video)
The team behind new drug candidates relies on collaboration
You could say that drug discovery is one long, exhausting audition. Thousands of compounds are systematically studied, tweaked, honed and tested, over multiple cycles, until a lucky few move forward in the pipeline.
Statistics vary, but on average only one in 5,000 drug candidates makes it through from invention to approval. In the US, the average successful drug takes 10 years to go from the lab to the pharmacy. At each stage of the drug development process, the drug costs more money and more time. Therefore, killing a failure early is as valuable as pushing through a winner.
It is the job of medicinal chemists, biologists, and pharmaceutical scientists, to build the most promising molecules, and they couldn’t do it without each other.
“It's iterative. The main idea is we build chemistry, build better molecules that are more efficacious, that are more stable, that actually have greater access to target tissues and organs. 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,” says Omar Aziz, Senior Director of Biology at Charles River’s Harlow site.
Omar is part of the Integrated Early Drug Discovery team in Harlow, a “new town” that borders London and is known for its sculptures. Back in March, just days before COVID-19 shut most of Europe down, we spent a day with Aziz and his colleagues, Russell Scammell (Director of Chemistry and Analytics), and Karen Williams (Director of Chemistry in Early Discovery), to talk about how molecules become drugs.
The vast majority of us probably never think about where that heart pill, diabetes medicine or chemo drug comes from, but the Harlow team thinks about it all the time. They are constantly in the hunt for that rare molecule among thousands that will make a difference to those patients with heart disease, diabetes or cancer. To get there they also have to deal with the roadblocks and failures.
“I'm from a family that's very much embedded in the medical profession. So, understanding things from that aspect is hugely important,” said Omar. “Not just because there are different ways you can deal with diseases, but there's always room for improvement. I don't believe there's a single drug on the market that couldn't be improved in some area or aspect of its properties.”
The development process starts with target validation – finding a “druggable” target that can be affected by a compound and have an effect on the disease in question. Next comes hit identification, a series of assays to determine whether the compound passes through screening cascades and interacts with the target. This phase can involve many different assays – from high throughput screening to nuclear magnetic resonance screens – to offer as much information as possible. Finally, the drug moves to the physiological assays in order to better understand whether it will have the desired effect in vivo.
“The end result is a drug that's in the market, that is hitting the target and this can be used on, on a day-to-day basis across a range of activities,” says Russ.
In reality a drug may pass back and forth through each phase as it is either validated, refined, or failed. At each step of the way Karen, Russ, Omar, and the rest of their colleagues keep each other abreast of successes and setbacks. Their collaboration is the key to keeping a drug moving through the labs in a fast and cost-effective manner, without sacrificing safety. Their respect for each other and their love for their work is obvious.
“I've always been interested in science from a very, very early age, all through my schooling, and chemistry just caught my attention,” said Karen. “We have really exciting science that we work on with our clients, and it's just nice to know that we can do that. Because we're a big company and we work across many sites, the collaboration piece is really important. It's just great to work with people from all around the world.”
“I always joke about chemists being the most optimistic people in the world, because it doesn't matter how many compounds they've made that just have not met the grade, they're still excited about the next one,” said Omar. “Whereas biologists, I would probably say are a bit more conservative, maybe a bit more pessimistic in their approach. They're going to look at it and think, it's just another compound. Is this going to be different from the last one? So, there's a lot of banter that goes on and I think it's taken in good humor with all parties involved,” says Omar
In those moments when they hit the jackpot and identify a winning candidate, it’s party time.
“What we frequently do in the UK – we’re a little bit obsessed by cake, so we normally have a cake party,” said Karen. “If there's a preclinical candidate nominated for a particular project team, we'll have a little celebration with the project team and invite the rest of the department along to join that celebration.”
“A massive iced cake,” said Omar.
“Just enormous,” Karen agreed.
In the end, the three agree that their work benefits from their close collaboration and their camaraderie. Working through setbacks and celebrating victories may not get covered in school, but those moments can make a job into a career and a passion.
“When you learn science at school, there's always some theory, there's some hypothesis,” said Karen. “What frequently happens in the drug discovery industry is that there are still those theories, but you're normally working on something which is unprecedented, on something that nobody else has worked on before, so there is not a straight path forward.”