For scientists developing new drugs, it’s hard to go wrong with targeting a family of receptors that regulate nearly every known process in humans. G protein coupled receptors (GPCRs) are found throughout the body, and research into their effects has so far yielded about 700 FDA-approved drugs. But that productivity comes with a problem. With so many molecules already targeting these receptors, scientists have struggled to find new ways and new places to attack them.
Robert Lefkowitz got 2012 Nobel Prize in Chemistry Thanks to his GPCR discoveries, he has developed new techniques to study these receptors and identify the molecules that bind to them in a way that has never been done before for drugs. The research forms the basis for South San Francisco-based Septerna, a new biotech company launched Thursday, backed by a $100 million Series A round led by Third Rock Ventures.
There are approximately 800 GPCRs in the human genome. Scientists began to understand them in the early 1970s. Lefkowitz, one of the pioneers in the field, has studied the nature and function of these receptors. GPCRs play an important role in how we taste and smell, Lefkowitz said. If you’re taking something for a stuffy winter nose right now, chances are it’s a GPCR-targeting drug. However, while scientists have found ways to drug many of these receptors, hundreds more have yet to be targeted.
Lefkowitz, a professor of medicine, biochemistry, and chemistry at Duke University and a co-founder of Septerna, isn’t looking for new drug treatments for GPCRs. Instead, his research focuses on finding new ways to study them. His Duke lab developed techniques to isolate receptors and study them outside cells, but in ways that also mimic the processes and environments they will encounter, such as their interactions with molecules. Some postdoctoral researchers in Lefkowitz’s lab who helped develop the techniques tried to convince him to seek funding to start a company. By his own admission, he did not accept the idea. As an academic, Lefkowitz said he thought it was best to stay in that silo. A call from a venture capitalist changed his mind.
Jeff Finer, a venture partner at Third Rock and now the CEO of Septerna, knew Lefkowitz from a decade ago when he was working at another biotech company. About three years ago, Finer said he called scientists at Duke University to find out what he thought of the GPCR field. At the time, Lefkowitz’s lab had been publishing its research, while the postdoc continued to consider the idea of a company. Finer’s call started the program. He proposes combining Lefkowitz lab techniques with computational techniques to advance drug discovery. The Septerna technology platform is called the Native Complex. In addition to isolating GPCRs, the technology screens molecular libraries for those that can bind to receptors.
“Get it out of the cell now and we can do a lot of things that were not possible before,” Finer said. “It opens up a toolbox of drug discovery techniques that were not previously available in this class. We can literally screen billions of compounds and find out which compounds attach to receptors in different ways.”
GPCRs facilitate binding to small molecules, making them very “druggable”. But currently available drugs bind to these receptors at known binding sites. In biotech parlance, these sites are well-formed. Native Complex finds other locations on the receptor where small molecules can bind to confer their therapeutic effect. These substitution sites are allosteric. By identifying allosteric sites on GPCRs, the space available for small molecules becomes larger, Lefkowitz said.
Septerna’s approach goes beyond finding new binding sites for small molecules. The conventional thinking about GPCRs, Lefkowitz says, is that these receptors are like on/off switches—drugs that bind to them either block the receptor or activate it. But binding to allosteric sites offers the potential to provide tunable effects, such as tuning rheostats.
Finer said Septerna will use its method to track GPCRs that are considered undruggable or difficult to drug. Where a peptide or biopharmaceutical has already addressed the GPCR, biotech companies may look for a way to hit that target with a small molecule. Where other small-molecule drugs already exist for GPCRs, Septerna may look for a way to deliver targeted drugs with different mechanisms of action. First, Septerna has five programs covering four therapeutic areas: Endocrinology, Central Nervous System, Metabolic Disease and Inflammation. The goal, Finer said, is to have three of these programs produce Phase 1 drug candidates “within a few years.”
There are other biotech companies seeking new GPCR drugs. Longboard Pharmaceuticals, a spin-out company of Arena Pharmaceuticals, is developing GPCR drugs for neuroscience indications. Longboard went public last year, raising $80 million. ShouTi is bringing computational methods to its GPCR drug search using technology from its co-founder, drug research software company Schrodinger. Shou Lai announced its own $100 million Series B financing in October last year.
In addition to Third Rock, other investors in Septerna’s Series A round include Samsara BioCapital, BVF Partners, Invus Financial Advisors, Catalio Capital Management, Casdin Capital and Logos Capital. Finer acknowledged that Septerna’s funding was larger than a typical Series A for a Third Rock-backed company. But he noted that the startup’s pipeline is more advanced, and the company will be working on multiple projects simultaneously. To support these plans, Septerna will expand its workforce, with the Finer project more than doubling this year to 40 to 50 employees.
“While this is a Series A, we believe this funding is sufficient to get us to the point where we can advance all parts of the pipeline,” Finer said. “We have a lot of great chances and we don’t want to drop any of them.”
Photo by Septina
