The magic of finding the perfect geometry

Daniela Angst still vividly recalls the moments of excitement before she would open the emails with the test results of the molecules she and the team of medicinal chemists at Novartis Biomedical Research in Basel had been working on to create a novel drug that could be both effective and gentle on patients. “I remember how every week we’d wait eagerly for the latest results,” Daniela Angst told live magazine in the spring of 2025. “The most exciting moment was finding out how well the new compound was binding to the target. The key thing we looked for was: Is it working or not? We measured the percentage of target bound by our molecules. The higher the percentage the better.” Angst and her colleagues had already been working on the compounds for several years – pioneering in a field that Novartis had never tackled before. They wanted to develop a covalent molecule that would inhibit Bruton's tyrosine kinase, or BTK, which had been identified as a potential target in immunology, able to treat diseases ranging from dermatological conditions to multiple sclerosis.

The journey that Novartis researchers had undertaken up to this point was already long. Initially, back in 2007, the team had started developing a reversible molecule to block BTK. And while this molecule had some strong properties, its water-repellent characteristic made it unfit as a meaningful drug development candidate. “We had beautiful molecules, very potent, very selective, with a very specific binding mode,” recalled François Gessier, who started to work on the project during its initial phase. “But these molecules were too greasy and too big to be made into real drugs.”

An untested route This is when the team led by Bruno Cenni and Robert Pulz, under the guidance of Martin Missbach and Rene Hersperger, decided in 2010 to take an untested route and instead of continuing to work on the conventional molecule – a compound that bound reversibly to BTK – opted to focus on a covalent binder. With this approach the team hoped to leverage some of the molecule’s strong properties and avoid the weak ones. “The idea was to deconstruct the molecule to improve its properties and then compensate for the loss of potency by introducing a covalent bond,” Daniela Angst said. “We had this excellent core, but the molecules were too big. Covalent binding gave us a way to shrink the molecule and keep it strong.” While developing a covalent inhibitor sounded convincing on paper, it came with some risks attached: Not only had Novartis never worked on such molecules outside oncology; the potential strength of covalent inhibitors is also their biggest weakness: their strong binding properties. If a covalent molecule is not specific enough, the risk is that it can attach to other parts in the body and cause side effects. “At that time, covalent inhibitors were a bit taboo outside oncology,” François Gessier recalled. “We had to justify why we were going in that direction.” But the team was confident of working with a covalent molecule because their original reversible compound had what it takes: high specificity. This meant the potential risk that the molecule could bind to other pockets outside the BTK target was relatively low. Their gut feeling proved right. Already their first prototype worked, said François Gessier. “This is quite rare, and we were certainly very lucky.”

Finding the right balance But despite the initial successful prototype as proof of concept, which created a lot of excitement, the team ran into uphill challenges because the compound was washed out too fast in the ensuing in-vivo animal trials. “It was frustrating. The chemistry worked on paper and in-vitro, but not in animals. That gap between the bench and biology was tough to bridge,” Daniela Angst said. What followed were years of hard work in which the team developed different types of molecules. While they were starting from the initial scaffold, they soon discarded this construct. They worked on different structures, focusing among other things on a variety of exit vectors. “We knew we had a great core that was very selective. And we just needed to find the right exit vector to reach the cysteine – the part in the BTK kinase that we wanted to target,” said Anna Vulpetti, an experienced modeler, who worked with Angst and Gessier on refining the molecule. “The compound has to reach the target with the right geometry, the right reactivity – not too fast, not too slow. This balance is the magic,” she summed up the journey on which they embarked. But the magic took years to achieve, Angst said, recalling that the team tested all sorts of ideas to reach their goal. “We spent a lot of time optimizing where and how to attach the warhead. It had to be reactive enough to bind, but not so reactive that it would disappear in the body before getting to the binding site.”

Anna Vulpetti sits on the staircase in Banting 1 during a short break from her work at the screen, where she analyzes the chemical properties of molecules.

Stronger than a magnet This was the time when Daniela Angst would eagerly await the results from the in-vivo tests, which for a long time would not provide the outcome they had longed for. But after about two years, the team made a breakthrough. “Once we saw the right balance of potency, stability, and selectivity, we knew we had something real.” What the team had achieved was the following, Angst explained: “Our warhead had a reactive part designed to find a specific amino acid in the target protein, in this case, a cysteine. When the drug gets close enough, the warhead reacts with the cysteine and forms a covalent bond, which is a strong, lasting connection.” To get the idea: It is stronger than a magnet. This bond is formed between a sulfur atom from the cysteine and a carbon atom from the drug. The connection stays active until the BTK enzyme disintegrates naturally in the body. This also has a positive effect for the patient: The drug can be administered in lower doses compared to conventional reversible molecules, which the team had started out on years before. Once they had hit upon the molecule, the team continued to work on other molecules. They were still eager to produce an even more efficient compound, which would have a high occupancy rate combined with very low exposure in the bloodstream. But as they progressed, it became clear that the initial hit was the molecule that had the fitting geometry to be developed into a drug – a feat that on average only happens once in 10,000 attempts. For the thousands of researchers at Novartis, this is an exceptional event even though the company, which since 1996 has developed more than 40 new molecular entities, is one of the industry’s most innovative and productive.

Once-in-a-lifetime experience For Daniela Angst and her colleagues working on a covalent binder was a rare experience. “I remember thinking how exciting it was to work on such a project because I had never worked on a covalent project before. Also to be able to block the target over an extended period without having the drug around in the circulation. I thought this would be really a great idea and was quite exciting at the time,” she recalled the early years of the project. When the team was finally able to create a covalent binder that also showed great potential in clinical trials, the team could not have been more excited. “Just knowing that someone might take this drug to have a better life – that’s what I wanted to achieve in my professional life. That’s enough,” François Gessier said, adding that this was the first time he had been able to work on a compound that made it to the clinic. “It’s a rare and special feeling.” Likewise, Anna Vulpetti cherishes the moment: “To see something that goes to Phase 1, 2 and 3 is extremely rewarding. This is why we do this job. Of course, there’s scientific satisfaction. But the real joy is when you know your molecule could help someone. That’s the goal we’re working toward.” For Angst, a scientist through and through, patients may not always be on the forefront when she is working in the lab concentrating on technical details and trying to solve elaborate riddles that no one has tried to unlock before. But when she has the chance to engage with the public and witness the fruit of her work, the magic of science is transformed into the magic of human emotion and purpose. “Last year, I gave a presentation, mainly focusing on the drug discovery side. At the end, I also shared the results from the Phase 2 study, which had just been released. After the talk, a man came up to me and said, ‘This is so exciting, when will it be available? My partner has urticaria, and I’d love to know more.’ In that moment I realized: This could really help people. And that was a powerful feeling.”

Research Teamwork. The magic of finding the perfect geometry Text Goran Mijuk. Photos Annick Ramp. Videos Stevie Michelsen. Creating novel molecules that can interact with relevant biological targets constitutes the daily routine for medicinal chemists. But this regular metric is magically transformed into a rare and exceptional experience once researchers find the perfect geometry that can make a difference for patients. More so when the chemical structure is part of a novel class of molecules.

“I remember how every week we’d wait eagerly for the latest results” Daniela Angst

“We had to justify why we were going in that direction.” Francois Gessier

Laboratory work with Francois Gessier.