In early 2017, John Tallarico and his team at Novartis started keeping tabs on intriguing research bubbling up in a handful of academic labs. Chemical biologists were reporting advances in a method for finding nooks and crannies on proteins for tethering drugs. They had real-world examples of how the technique, which uses chemical probes to map out binding pockets on proteins, could be used to tackle bad actors that have long vexed medicinal chemists.
One particularly rich vein of work was in the labs of Daniel Nomura, a scientist at the University of California, Berkeley. Nomura had already collaborated a bit with Novartis, and he soon found himself talking to Tallarico, the head of chemical biology at the Novartis Institutes for BioMedical Research, about how to expand the relationship.
Tallarico’s interest had been piqued by how many of these “hot spots,” as Nomura calls them, on proteins were being discovered. Despite decades of toil, drug developers have been able to get traction against only about 15% of the human proteome; the chemoproteomics methods from Nomura and other labs promised to crack open the “undruggable” 85%.
When their chats began, Tallarico was imagining a modest project involving a few postdocs in Nomura’s lab. The big pharma company was interested mainly in learning how to replicate the experiments Nomura’s team was conducting so it could access undruggable proteins itself.
But as Nomura talked with colleagues at Berkeley, and they in turn talked with Novartis, grander ideas began to percolate. By October, the Novartis-Berkeley Center for Proteomics & Chemistry Technologies was born.
The center is virtual, with academic participants scattered across the Berkeley campus and Novartis participants spanning the U.S. coasts. In addition to Nomura, Berkeley chemists Christopher Chang, Tom Maimone, and Dean Toste are in the mix. The Berkeley researchers now have access to experts in informatics and computer-aided drug design as well as Novartis’s vast libraries of compounds. Novartis, meanwhile, has assembled a team with know-how in chemical proteomics, biology, and chemistry.
The center aims to wed chemistry and biology to explore new drug mechanisms and targets and to broaden Nomura’s platform to develop drugs against a wide swath of proteins.
Novartis won’t comment on drug targets the partners are pursuing, but the center’s current focus is on oncology and infectious disease. Similarly, the partners have not said how much money Novartis is committing to the center. But the Berkeley scientists say even some of their riskier ideas—the kind that can be hard to sell to industry—are being supported.
The setup dovetails nicely with Novartis research chief Jay Bradner’s larger vision for open research innovation. A chemical biologist himself, Bradner left academia in 2016 to join the big pharma firm. In the past two years, he has challenged Novartis scientists to come up with creative ways to access cutting-edge technology.
The Novartis-Berkeley center will work on speeding and broadening efforts to discover drugs against difficult targets. That means expanding both the number of proteins that Nomura’s platform can broach and the kinds of molecules that interact with them.
Toste and Chang are key to the effort. To map hot spots on proteins, Nomura relies on chemical probes that react with select amino acids, such as cysteines or lysines, on the surfaces or crevices of proteins. The approach has found new drug targets, but the chemists would like to take advantage of any amino acid found inside a protein binding pocket.
“Is it going to be easy?” Toste asks. “If it was easy, it probably would have already been done.”
Indeed, designing new chemical probes is a daunting task. The reagents not only need to work in a cell but must also display very specific properties to be useful in Nomura’s platform.
Toste and Chang had already made headway on methionine when the talks with Novartis started. But their original probes were designed for conjugating proteins, not for Nomura’s platform, Toste says. That requirement introduced a long checklist the probes must fulfill.
Still, progress has been swift. Toste and Chang’s methionine-functionalizing probes are in a second generation and have already yielded one intriguing drug target. Toste says the team is now working on a tyrosine probe.
In addition to expanding the number of amino acid-targeting probes, the team is looking to nature’s rich tapestry of molecules for inspiration in discovering new drug candidates, drug targets, and protein binding sites. Natural products have long been studied for their ability to kill bacteria or cancer cells, but often the molecules are too toxic, too unwieldy, or too tough to synthesize. Moreover, scientists often don’t know how they work.
That’s where Maimone comes in. Nomura can figure out how natural products work and pass them over to Maimone to turn them into tools, make derivatives, or figure out which part of the molecule is interacting with the protein—a useful starting point for designing a new drug.
“He looks at structures differently than a lot of chemists,” Tallarico says of Maimone, “and he has a particular affinity for building molecules you’d think would be unstable or reactive.”
The natural product work could be relevant in a burgeoning area of drug development called targeted protein degradation, in which bifunctional small molecules bind both a bad-behaving protein and ubiquitin ligase, ultimately pushing the protein to be broken down in the proteasome.
The degrader molecule needs merely to bind to a protein, not modulate its activity like a typical drug does. As Maimone points out, the early degraders were based on natural products. Meanwhile, Nomura’s chemoproteomics platform is likewise primed to find molecules that just bind to proteins without necessarily inhibiting them.
While Novartis works with Berkeley to expand use of the technology to new drug targets and, potentially, new drugs, others are plugging away at the same problem.
Last year, a biotech company with a similar technology was spun off of the Scripps Research Institute California labs of Benjamin Cravatt, who also happened to be Nomura’s postdoctoral adviser. The firm, Vividion, attracted $50 million in financing and last month established a lucrative drug discovery pact with Celgene.
Competition in this field will surely get tougher, but Novartis is encouraged by how fast the collaborators are making progress. “The success so far has catalyzed us to think about our own process,” Tallarico says.
The Berkeley group has made progress with its screens of a small set of compounds. Novartis is now trying to design its own version of Nomura’s setup so it can be applied to internal projects. “We’re a company with deeper resources around small molecules,” Tallarico points out.
For Nomura, the interactions with Novartis are sparking ideas for experiments he wouldn’t have thought of on his own. “I almost feel bad getting all these ideas from them and running with it,” he laughs. “But it’s been really fun.”