By Yoyo Ma, Winter 2023.
The realms of over the counter drugs and laboratory research seem disparate upon first glance, but one of the most beautiful parts of the drug development and discovery process are the years of struggle and strife. One such discovery is the story of Bristol Myers Squibbs’ psoriasis drug Sotyktu, which targets a never-before-targeted enzyme called TYK2. TYK2 is a type of enzyme which is able to turn on the activity and function of other proteins — but how do scientists translate this knowledge in order to find and treat a novel target like TYK2, and what exactly goes into the making of a billion dollar molecule?
The journey of Sotyktu starts with the characterization of the TYK2 enzyme. TYK2 had been identified in 1990 through multiple genome-wide association studies, nearly 35 years before the development of Sotyktu. It was found to be involved in and causal to a range of different autoimmune diseases — like Crohn’s, psoriasis, and rheumatoid arthritis — and was thus to companies like Bristol Myers Squibbs.
Because a lack of TYK2 was found to cause diseases like psoriasis and IBS, scientists at BMS would need to find a drug that would keep the enzyme activated. However, the first challenge was the same challenge that had discouraged other companies’ TYK2 work: there were infinite possibilities of what could bind to TYK2, but only a select few could bind to only TYK2. TYK2 happened to be structurally similar to the JAK family of kinases, and binding of these JAK enzymes were correlated to higher rates of infection, blood clotting, and other negative side effects. This meant that BMS would need to find drugs that were specific enough to selectively bind TYK2, not JAK, and directly conducting an experiment on what molecules bound TYK2 risked accidentally binding to JAK as well.
Their solution was twofold. First, they knew that TYK2 was one of many enzymes in an anti-inflammatory pathway (meaning that the pathway helps reduce swelling, fever, and pain in the body), so instead of testing how well drug candidates could affect just TYK2, they decided to test how well drug candidates could affect the whole pathway. Second, they limited their possible drug candidates to molecules that were ineffective against JAK. The combination of these two strategies allowed BMS to look for drug candidates that were able to affect the entire pathway but also were unable to bind to JAK enzymes.
The scientists used this procedure to test about 8000 small molecules, and found a collection of hits that bound to a specific site, called a domain, of TYK2. However, this finding uncovered a second challenge: these hits did not bind to the enzyme’s well researched active domain, but rather bound to a non-functional “pseudokinase” domain with an unknown activation mechanism. Furthermore, there were no pseudokinase drugs on the market, so the clinical implications were also unknown. They were in uncharted territory. Thus, the scientists sought to understand how the pseudokinase domain could regulate the activity of the whole TYK2 enzyme even though it was a nonfunctional site. They characterized how each small molecule physically binds to the domain, how the cell can stabilize the pseudokinase domain, what the crystal structure of the molecule-domain complex looks like, and why hits could specifically bind to TYK2’s pseudokinase domain and not a JAK pseudokinase domain. Through all of these studies, the BMS team found a single hit that best bound to TYK2 and not JAK, and could hypothesize that the pseudokinase domain on TYK2 was allosteric: when a hit molecule bound to the site, it changed the shape of the kinase and activated its function.
With this success, BMS could begin mouse studies of their top hit molecule. But a third challenge arose. One of the molecule’s weaker side methyl chains tended to fall off, decreasing the molecule’s ability to bind efficiently and selectively to TYK2. To prevent this issue, the scientists brilliantly used a widely known, but rarely used strategy: deuteration. They replaced the hydrogen atoms in the methyl group with a heavier hydrogen atom with two neutrons instead of one, called deuterium. The deuterium substitution made the methyl group heavier, and thus less likely to fall off because it reacted less. This deuteration approach was one elegant refinement of many to transform their work from a small molecule hit to a stable, trustworthy drug, and after a few more small adjustments to their molecule, Sotyktu was declared and passed into Phase I clinical testing at the start of 2015.
The development of Sotyktu is an incredible story of how a target becomes a commercialized drug, and how scientific research can reach people. However, it is one story of many: recently, Sotyktu has reemerged in biotech and pharma headlines, since a new TYK2 drug candidate claiming that it can top Sotyktu was bought by Takeda Pharmaceuticals for upwards of $6 billion. As such, the TYK2 enzyme gets revisited in the lab, a new therapeutic gets developed, and the cycle of scientific discovery and innovation continues.
[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3748334/