Rewriting the drug discovery playbook

Published on 05/12/2022

In the history of medicine, it is rare to find drugs that operate in a completely new way. But this is what a serendipitous finding about an old drug revealed several years ago. Since then, drug researchers around the world have been racing to develop new drugs using this strategy – an endeavor which a team of researchers at Novartis may be among the first to accomplish with one of their most recent immuno-oncology drug candidates.

This investigational small-molecule drug operates by sending a disease-triggering protein, named Helios, to the cell’s garbage disposal system, where it is consequently destroyed. This strategy, called targeted protein degradation, was proposed back in the late 1990s and has since been accelerated at Novartis when Jay Bradner, President of the Novartis Institutes for BioMedical Research (NIBR), joined the company in 2016.

The process could be revolutionary because it offers the possibility of specifically eliminating (through degradation) any protein linked to a disease. This includes a multitude of previously undruggable proteins – biomolecules that have been impervious to drug discovery efforts to date. Furthermore, it offers a path to fundamentally rewrite the playbook on drug discovery.

Using chemistry to understand biology

“The whole promise of chemical biology is that we’re not afraid to tackle the undruggable,” says Ulrich Schopfer, who leads Chemical Biology and Therapeutics at NIBR in Basel, Switzerland. “We drill into the molecular details of biology and human disease to discover new targeting concepts and drug leads.”

As part of the chemical biology approach, a whole string of specialized scientists are working together to create small molecules that are designed to help them learn more about and control protein activities.

Structural biologists use methods like X-ray crystallography and cryo-EM – roughly comparable to super powerful microscopes – to help unveil the shape of these proteins. Medicinal chemists, meanwhile, design a variety of molecules that bind in different ways until they find the best fit –and possibly the starting point for drug optimization.

While many drug discovery efforts focus on molecules that shut proteins off by blocking their binding pockets, much like a key that fits into a keyhole, the relatively new strategy of targeted protein degra­dation requires a more sophisticated approach.

Instead of one, the small chemical molecules need to bind to two proteins, i.e., the disease-triggering protein that researchers want to degrade and the protein that will get the removal process started.

In 2010, a team in Japan did a chemical biology experiment using a chemical tool to understand the mechanism of thalidomide – a drug that has been in use since the 1950s – which shed light on this complex process.

Thalidomide and its derivatives, the researchers found, build bridges that connect certain cancer-provoking proteins with the protein complexes that then send them off for removal.

While this was an exciting finding on its own, the fact that thalidomide built bridges with so-called transcription factors was even more surprising.

Transcription factors play a key role in disease, particularly cancers. Humans have nearly 1600 different transcription factors. But these proteins have largely been beyond the reach of conventional drug discovery efforts because they are notoriously difficult to target as they don’t have druggable binding pockets. In science lingo, these proteins have been described as undruggable.

In 2014, the pieces of the puzzle came together further when Nico Thomae, Senior Group Leader at the Friedrich Miescher Institute in Basel, published his group’s research showing the molecular structure of the protein complex that binds thalidomide. Thomae specializes in transcription factors and this work showed the atomic details of how thalidomide brings everything together to set the removal process in motion.

Following up on these potentially transformative discoveries, two investigators at the Cambridge headquarters of NIBR, chemist Rohan Beckwith and biologist Jonathan Solomon, proposed to start a project in 2015 to further explore the findings surrounding thalidomide.

“The project was like an embodiment of chemical biology,” Jonathan Solomon describes the technical scope of the project. “We were using a small molecule to bring two proteins together with the hope that it will cause a biological change – in this case protein degradation.”

Soon after Beckwith and Solomon started their work, they began looking for additional proteins – and therefore diseases – that they could target using this new strategy. This led them to a transcription factor drug target called Helios, which had also attracted the attention of NIBR’s Immuno-Oncology (IO) group.

When Beckwith and Solomon shared their ideas with the IO group, both teams immediately realized that a potential collaboration could be an interesting oppor­tunity to apply a novel drug discovery approach to a target that had the potential to help patients with a wide range of cancer types.

“The IO group was extremely interested and that really propelled the program forward,” says Eva d’Hennezel, who joined the project as one of their IO experts and Senior Principal Scientist in Immuno-Oncology.

With the support of the IO group and Global Discovery Chemistry, the project got officially kicked off in the summer of 2016.

“It was a really exciting time because, with every experiment, we basically learned something amazing about degraders and it was just such a time of rapid exploration and growth,” Jonathan Solomon remembers.

In the spring of 2017, the team identified the first potent Helios degraders, one of which became the eventual clinical candidate. At this point, the project was fully transferred from the chemical biology group to Oncology-IO and Global Discovery Chemistry to take on the work of progressing candidates towards the clinic and developing alternative degraders.

Thanks to strong collaboration and alignment across all line functions involved in the effort, the drug candidate was ushered to the clinic in roughly two years – nearly record time in drug discovery.

“It has been amazing to see the power of bringing together the multidisciplinary drug discovery expertise from all the line functions involved with the project and turn a tool compound into a drug candidate with the appropriate efficacy and safety properties,” says Simone Bonazzi, one of the team’s co-lead chemists and Associate Director in Global Discovery Chemistry. “It felt like we were the tip of the spear that included the entire NIBR team and everyone was backing us.”

Meanwhile, the new molecule showed high effectiveness in preclinical models. One of the factors allowing the successful discovery of the selective Helios degrader as well as its efficiency was the focus on finding the key biological step in the process.

“There has been this explosion of similar research worldwide, but we’ve seen that others often look only at the final step – the degradation of the protein,” says Simone Bonazzi. “At NIBR, we followed a different approach and looked at the preceding steps of the process, which made it possible to identify several promising starting points for the lead optimization effort.”

While the ongoing clinical trial aims to collect preliminary evidence on the potential benefits for patients with advanced solid tumors, researchers are convinced that targeted protein degradation has a great future and that the recent efforts to put a full platform in place will become the foundation for many new targeted protein degradation programs within NIBR.

“Targeted protein degradation has reset expectations of what small molecules are capable of achieving,” says Bill Forrester, Global Co-Lead of the Targeted Protein Degradation Initiative. “The lessons from the Helios project have led to substantial strategy shifts and an entirely new level of appreciation for how chemical biology can revolutionize drug discovery through new lines of attack on critical targets that were until recently considered out of reach.”

For Ulrich Schopfer, the success story with Helios is also another validation point for chemical biology.

“The concept of chemical biology was coined around the realization that chemistry could be a useful tool to understand biology,” explains Schopfer. “It has proven immensely powerful in the last three decades for giving researchers the ability to understand biology at a molecular, and even atomic, level – a fundamental starting point for drug discovery efforts. Chemical biology continues to be a powerful agent in drug discovery with the potential to rewrite the drug discovery playbook.”