Finding the right molecular structure.
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Team spiritComing full circlePublished on 18/12/2023
In 2005, Christopher Brain had just moved from the United Kingdom to the United States with his family to continue his career at Novartis Biomedical Research Research in Cambridge, when he had the chance to embark on a new research topic as a project team leader.
It was a great and somewhat rare opportunity, one which the medicinal chemist, who had started his career at Novartis in 1996 after finishing his Ph.D. and master’s degrees at the Universities of Manchester and Oxford, did not want to pass up.
The new opportunity was in the field of the so-called cyclin-dependent kinases, or CDKs, which were discovered about two decades earlier and had helped scientists shed light on cell division.
“It was a hot topic at the time and a contested area too,” remembers Chris Brain, who is still active as a chemistry leader in Cambridge. “But I felt intrigued by it and very motivated to pursue this road.”
Nobel beginnings
Just a few years earlier, in 2001, Lee Hartwell, Tim Hunt and Paul Nurse had received the Nobel Prize in medicine for their research into cell division, concentrating their work on understanding the underlying genetic structure of this crucial life process.
In the 1970s Hartwell studied baker’s yeast. He realized that the cell cycle stopped at elevated temperatures and singled out 12 genes involved in the process, including CDC28, which starts the cell cycle.
Nurse followed up. He not only found a crucial yeast gene that regulates the entire cell cycle, but also showed that the corresponding human cell cycle gene works perfectly in yeast. With this he also proved that this particular cell function, known as CDK, had been conserved for nearly 1 billion years.
Hunt later found the protein cyclin, which regulates the function of the CDK molecule, kick-starting the entire cell cycle process. When they were awarded the Nobel Prize in Stockholm, the presentation speech mentioned the following: “It is now almost 50 years since the structure of the DNA molecule was discovered, leading to a molecular explanation of how a gene can make a copy of itself. With the discoveries of CDK and cyclin we are now beginning to understand, at the molecular level, how the cell can replicate itself.”
Toxic intermezzo
However, it took nearly two decades before researchers were able to translate this knowledge into a therapy. In the 1990s, pharmaceutical companies had already started to use the new scientific insights to combat cancer. The idea was to inhibit the cell cycle, which had spun out of control in some cancer patients.
Early results, however, were disappointing. This was because researchers struggled to understand which CDK complex they should target. Researchers had come to learn that in humans the cell cycle involved not one but more than 10 CDKs – each was named with a specific number. Worse, blocking some of them led to toxic results.
As the understanding of the underlying biology continued to grow, CDK4 and CDK6 – two kinases that were part of this complex cycle – were identified as possible targets. But any potential inhibitor would need to be designed in such a way as to avoid interfering with CDK1, which, as researchers had found out, was causing toxic reactions.
Finding the right key to this riddle was the central challenge faced by Chris Brain and the new project team in 2005. A group of highly dedicated scientists was assembled with the goal of inventing a selective compound which would do the trick.
