Jnana Therapeutics tries to take on an untapped class of proteins

Every Monday night—travel schedules permitting—Stuart Schreiber and Ramnik Xavier meet with a small team of researchers at Jnana Therapeutics, a company they cofounded, to discuss the start-up’s latest discoveries about solute carriers (SLCs), molecule-moving proteins encoded by a large family of more than 400 human genes. There’s a lot to learn. In an look at the field in 2015, drug discovery experts from industry and academia said that SLCs are “the most neglected group of genes in the human genome,” even though SLCs appear to be involved in just about every bodily function.

The membrane-embedded proteins move ions, metabolites, neurotransmitters, and more across cells and between cellular compartments. But a long-standing lack of tools, and interest, in SLCs has made it difficult for the few scientists who do study them to tease out exactly what many of them do and where they do it. Recently, as scientists have discovered links between more than 100 different SLCs and a variety of diseases, it has become clear that they’re not getting the attention they deserve (Cell 2015, DOI: 10.1016/j.cell.2015.07.022).

Schreiber and Xavier grew interested in forming a company around SLCs after their labs at Broad Institute of MIT & Harvard independently discovered ties between SLCs and disease. For instance, Xavier helped identify one mutant SLC involved in inflammatory bowel disease (Gastroenterology 2016, DOI: 10.1053/j.gastro.2016.06.051). And Schreiber helped find variants of another SLC that partially explains the increased prevalence of type 2 diabetes in Mexico (Cell 2017, DOI: 10.1016/j.cell.2017.06.011). As they discussed their work, it became clear that no one was attempting to drug the protein family methodically. So in January 2017, they founded Jnana (pronounced ja-na-na) to change that.

The duo recruited Joanne Kotz, previously a director at Broad, to become employee number one and Jnana’s president. She was followed by Joel Barrish, the former head of discovery chemistry at Bristol-Myers Squibb, who joined as chief scientific officer. Within nine months of forming, Jnana had secured $50 million in financing from a syndicate of life sciences and corporate venture capital firms. Now, the start-up is growing steadily, housed inside the Boston headquarters of Vertex Pharmaceuticals, the successful drug company that Schreiber helped found 30 years ago.

At a time when many biotech companies are focusing on so-called undruggable proteins, or ones that offer no clear footholds for traditional drugs to latch on to, Jnana stands out for targeting a class of proteins that look readily druggable. “They are professional small-molecule movers, so they inherently have binding sites that are going to be amenable to small-molecule drugs,” Kotz says.

The links tying SLCs to a flurry of different diseases have helped make a case for an ambitious effort to begin studying the proteins in more detail, Kotz says. But a number of factors still hinder productive drug discovery in the class. “These are tricky proteins to work with, and not a lot is known about them structurally,” she adds.

Even though drugs exist that block the activity of about 20 different SLCs, many of them were discovered without the drug companies knowing much about the SLC they targeted. For instance, reserpine was first used as a tranquilizer in the 1950s and later as an antipsychotic and antihypertensive drug. Reserpine’s target, an SLC found in neurons, wasn’t discovered until 1992.

Another example is the antidepressant Prozac. When the drug was approved for sale in the U.S. in 1987, scientists knew it selectively inhibited serotonin reuptake in neurons. But its primary target, an SLC called the serotonin transporter, wasn’t elucidated until 1991. That SLC’s structure was resolved only two years ago (Nature 2016, DOI: 10.1038/nature17629).

Although scientists have determined the structures of only a handful of SLCs, many more could be on the horizon, as methods like cryo-electron microscopy make inroads in resolving structures of membrane proteins. Jnana will have to lead the way in creating assays and small-molecule libraries optimized for studying the proteins.

The start-up’s name is a Sanskrit word meaning knowledge or wisdom gained through experience, Kotz explains. It’s an apt description of what the group will need to achieve as it begins to build an SLC drug discovery program from the ground up.

“We are really the first company to take a holistic approach” to SLC drug discovery, Barrish says. “Until now, it’s always been ad hoc.”

The state of SLC science reminds Barrish of the early days of drug discovery for two other large classes of proteins: enzymes called kinases and membrane proteins called G protein-coupled receptors (GPCRs). Today, both are staple members of drug discovery programs, largely thanks to advancements in understanding the proteins’ structures. “I’d say five years from now, the area of SLC structural biology will be at the same place GPCRs are today,” Barrish adds.

Scientists at Jnana aren’t the only ones with such high hopes for SLCs. Giulio Superti-Furga, a researcher at Medical University of Vienna, also sees SLCs as one of the next major drug discovery frontiers. “In 10 years, I think SLCs will occupy one-fourth of the new drug targets for small molecules,” he says. “We still have a lot to understand, but it will catch on.”

In fact, Superti-Furga is coleading a new SLC research initiative called Resolute, which will pool resources from six academic institutions and seven companies—including Bayer, Boehringer Ingelheim, Novartis, and Pfizer—to study the SLCs whose functions are still unknown and develop new tools to accelerate SLC research. The five-year project kicked off in July 2018, with about $27 million in funding, roughly half from industry partners and half from the European Union-backed Innovative Medicines Initiative.

“I hope that this could be the start of an era where the SLC protein family is more systemically studied,” says David Hepworth, a vice president of medicinal chemistry at Pfizer’s R&D site in Cambridge, Mass.

So far, the structures of SLCs appear to be more diverse than those of the kinase and GPCR families. For instance, all kinases perform similar enzymatic reactions, and all GPCRs have a canonical structure that weaves in and out of the cell membrane seven times. SLCs, in contrast, bind many kinds of molecules and have structures of varying sizes, making systematic SLC drug discovery complicated, Hepworth says.

Jnana isn’t disclosing any specifics about its SLC targets yet, but it is focused on inflammatory and autoimmune diseases. And because the proteins are the gates for controlling the flux of metabolites into cells, Kotz says SLCs could be new targets for regulating the immunometabolism pathways in cancer.

Although it will likely be years before Jnana is able to prove its theory that SLCs will be the next big thing, if the company is right, it’ll have a head start. “SLCs are just calling out for a small-molecule approach,” Barrish says. “This is an area that is going to explode.”