Translating the cycle of life

Published 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.

The stakes were high. Other companies were already working on similar projects, and Novartis wanted to be among the early movers in the field as it also became increasingly apparent that CDK4 and CDK6 played a major role in most cancers.

“This was a massive undertaking,” Brain remembers, as both CDK4 and CDK6 are “key regulators of cell division that are dysregulated in more than 80 percent of human cancers.”

Novartis invested the full weight of its research capability, trying to approach the problem from various angles and leveraging the full force of its scientific talent base.

Besides using high-throughput screening and tapping into the wealth of experience in kinase research – several key cancer treatments of Novartis are kinase inhibitors – the team also collaborated with Cambridge, UK-based Astex Pharmaceuticals to use cutting-edge biophysical research approaches.

“The really great thing about this project was that we had the right mindset from the start to work hard on the problem and use the best science to meet our goal,” Brain says. “This allowed us to take a very close look at the underlying biology and chemistry, really understand the mechanisms of action and work towards a targeted therapy.”

Collaboration and going the extra mile were also instrumental. The drug discovery team, which at times consisted of around 40 people, gained an early clue from another Novartis research team, which had made a molecule that inhibits CDK1 and CDK2.

Although the molecule was not exactly what the team was hunting for, the scaffold, which denotes the basic molecular structure scientists use to develop a drug compound, was a starting point and even inspired colleagues who were not formally assigned to Brain’s team to develop it further. “I think this is really the secret of success, to have people working together who are entirely driven by science and progress and want to achieve the best results,” Brain says.

Hard science

This spirit of collaboration worked almost like a potion. Roughly two years after Chris Brain and his team started on the project and after many setbacks, they synthesized a molecule, which would later be developed into a fully functioning cancer treatment targeting specific forms of breast cancer.

But despite the early success, the team’s work had only just started. Given the toxicity in earlier trials with non-selective cell cycle kinase inhibitors, the team had to test the tolerability, efficacy and many other key aspects of the compound to understand if a highly selective compound could be turned into a new medicine.

For this, the team also went beyond the call of duty, trying to understand the underlying mechanism of the molecule and how it interacted with the kinases, especially CDK4, for which the structure needed to be established.

“We recognized very early that the protein surface we were targeting had a high degree of three-dimensional conservation with off-targets,” Brain says. “The hurdles we faced to obtain crystal structures, i.e., three-dimensional atomic-level information, were significant, as this target had been attempted by many groups in the past.”

But the resilience paid off. “Ours was the first team to gain a structural understanding of the molecular interactions that favor CDK4/6 selectivity over CDK1 and CDK2, and this culminated in the world’s first crystal structure of CDK4 in complex with its cyclin partner,” Chris Brain explains.

“Of course,” Brain admits, “there were many ups and downs during the project. As with every drug discovery program, the end could have come at any time. Anxiety and tension were perpetual companions. But I believe that in this case we had luck on our side also because we paired collaboration with scientific exactitude.”

After the molecule worked in animal models and after Phase I trials went well, the compound was transitioned to Phase III trials thanks to the convincing data that had been accumulated since the start of the research project.

Taking this risk was worthwhile. A pivotal Phase III trial, in which over 600 patients were enrolled, was a success, showing that the molecule in combination with another therapy reduced the risk of tumor progression, paving the way for the medicine to be approved.

Twelve years of hard work had come full circle. And the result was also making good on hopes expressed almost two decades earlier when the Nobel Prize Committee said that the fundamental discoveries by Hartwell, Hunt and Nurse would have “a huge impact on cell biology with broad applications in many fields of biology and medicine.”

“Considering that the early research dates back to the 1970s, it has taken a very long time to translate this basic knowledge into a drug,” says Chris Brain. “But this is the nature of drug discovery. It takes a lot of time, patience and contributions from diverse disciplines. Most of all, it requires the right mindset of collaboration, teamwork and determination. Together, this is what makes progress in drug discovery possible in developing treatment options for patients who need them.”

New findings

But drug development is even more complex than this. Years after Brain and his colleagues successfully developed a new molecule that showed effectiveness in breast cancer patients, new trials revealed that the molecule was also able to help patients who so far had no access to the drug.

“This was a great finding that our colleagues from clinical development have achieved and shows how complex the understanding of human biology is,” Brain says. “Most of all, it also shows how long the timelines actually are to establish robust medical findings.”

Even as the day-to-day activities in the lab can sometimes feel frantic, it can take decades of diligent research to make a difference for patients. Against this background, Novartis is now continuing its work on the molecule discovered by Brain and his team as it wants to build on the knowledge gathered during the decades of hard work.

“We are now looking into the possibility to build on the knowledge we have acquired in this particular field,” Brain says. “With this we will continue to build on findings that we have discovered over many years.”