You might say the recent launch of Interline Therapeutics comes down to community. There is the community of veteran biopharma executives and researchers who recently completed a $92 million in Series A financing that brought the nearly year-old startup out of stealth mode.

There’s also the community at Foresite Labs, the entrepreneurial innovation hub of Foresite Capital where venture partner and Interline co-founder and CEO Zachary Sweeney, PhD, incubated the company.

Interline says it will stand out among protein-focused drug developers by focusing on systematically mapping and modulating protein communities by applying genomics, proteomics, structural biology, and computational chemistry. [Interline Therapeutics]
Most important to Interline, there are the interactive networks of dynamic protein-protein interactions (PPIs), or “communities,” through which proteins function, but whose workings still remain largely unknown to researchers. Interline aims to elucidate those protein communities as it fights common diseases by defining their molecular mechanisms as driven by genetic variants.

“We are focused on genetic variation that’s associated with inflammatory diseases and cancer, specifically genetic variation that affects the structure of protein communities,” Sweeney told GEN Edge. “There’s a lot of genetic information that hasn’t been actionable because we haven’t understood protein communities in both of those areas. There’s also an element of the immune response that relates to how the cell changes the structure of protein communities in response to stimulation.”

While the Human Reference Interactome Map (HuRI) currently tallies 64,006 interactions among 9,094 proteins (up from 52,569 a year earlier), a 2020 review article found more than 645,000 disease-relevant PPIs in the human interactome, with drugs developed for just 2% of these targets. Current FDA-approved drugs are directed to only 754 separate human proteins directly related to the mechanism of action for the drug, according to DrugBank Online data shared by the Human Protein Atlas.

Most other disease-relevant PPIs in protein complexes, such as transcription factors and many other signaling proteins, have been deemed undruggable and are still poorly understood.

Interline has launched collaborations with Memorial Sloan Kettering Cancer Center (MSK) focused on computational chemistry, and with the University of California, San Francisco, (UCSF), centered on protein mapping.

At MSK, computational chemist John Chodera, PhD, associate member and laboratory director of the Sloan Kettering Institute, is partnering with Interline to study how small molecules modify protein movement, a key to protein-protein interaction. MSK has intellectual property rights and associated financial interests related to Interline through licensing agreements, the company has disclosed.

“With UCSF, we’re mapping protein communities and how they’re dysregulated in inflammatory diseases,” Sweeney said, through a collaboration with Nevan J. Krogan, PhD, professor, cellular and molecular pharmacology and director of UCSF’s Quantitative Biosciences Institutes. “We’re building an exciting computational chemistry pipeline.”

Six-program pipeline

That pipeline includes six small-molecule programs that Interline is developing. Sweeney wouldn’t discuss specific targets or indications, but offered that “the lead programs relate to innate immune response, largely, and we think we’ll have application in inflammatory bowel diseases and lupus.”

“We hope to be in the clinic in 2–3 years,” he added. “There’s an element of discovery pharmacology using protein-expressing proteins, looking at the ways that small molecules bind to these proteins and change the way that they interact.”

“Once we understand how protein communities are disregulated in disease and cellular experiments, then we have the opportunity to use advanced biophysics protein expression, Cryo-EM [cryogenic electron microscopy], and other new technologies,” Sweeney said. “They allow us to identify new leads that modulate these protein communities and really confirm that the drugs that we discover and develop effect have the desired effect on protein communities.”

Interline joins a growing number of startups in applying protein analysis toward drug discovery and development.

On May 5, Eikon Therapeutics—whose CEO Roger M. Perlmutter, MD, PhD, was previously an executive vice president with Merck and president of Merck Research Laboratories—completed a $148-million Series A financing. Eikon’s drug discovery platform is designed to elucidate the behavior of proteins in live cells using super-resolution microscopy, a technology developed by company co-founder Eric Betzig, PhD, and collaborators, for which they were awarded the 2014 Nobel Prize in Chemistry.

Also on May 5, the three-year-old startup BridGene Biosciences closed on $12 million in Series A financing to develop its IMTAC™ (Isobaric Mass Tagged Affinity Characterization) chemoproteomic platform toward discovering and developing small molecules for high value, yet traditionally undruggable targets. BridGene said it would use the proceeds to expand the company’s proprietary covalent library to discover small-molecule ligands for a broader range of targets, advance existing oncology programs and enhance operations.

Three-pillar platform

Interline says it will stand out among protein-focused drug developers by focusing on systematically mapping and modulating protein communities by applying genomics, proteomics, structural biology, and computational chemistry. The company says its precision medicine platform has three pillars or critical areas:

  • Genomics: Prioritizing genetic variants that alter protein communities.
  • Communities: Identifying the molecular mechanisms through which variants change protein communities, using machine learning.
  • Modulators: Discovering and characterizing drugs intended to reshape these communities.

“It’s a really exciting moment for somebody who’s been thinking about proteins in the way that they work in these communities for some period of time,” Don Kirkpatrick, PhD, vice president, CTO with Interline, told GEN Edge.

Kirkpatrick met Sweeney when they both worked at Genentech, and where they established an active collaboration focused on interrogating protein communities. The pair co-authored a 2012 paper published in Science Translational Medicine that shed light on how leucine-rich repeat kinase 2 (LRRK2) kinase activity explained the molecular mechanisms of Parkinson’s disease, in part using quantitative mass spectrometry.

Since then, Kirkpatrick observed, mass spec has developed to where researchers can generate systematic quantitative data, not just about the abundance of proteins but about various peripheral relationships that shape how cells work.

But it’s not an exclusive technology, he said, as seen by the recent emergence of non-mass spectrometry proteomics technologies—and the companies developing them.

“All of this culminates in bringing together data that’s been systematically acquired, so that we can apply machine learning and advanced computational methods to squeeze value out of it,” Kirkpatrick said.

Value proposition

“That value that we’re aiming to grab is an understanding of where within a protein community we want to target in order to successfully impact common disease that’s driven by genetic variants—then to have that information to understand when we do hit that target or those targets, are we being successful in defining what success looks like on a molecular level, so that we can be precise in what we’re trying to deliver?”

Last year, while still at Genentech, Kirkpatrick and Hanna G. Budayeva, PhD, a senior scientific researcher at Genentech, published a review article in Nature Reviews Drug Discovery describing how mass spec helps researchers decipher the complex relations between protein communities in drug development, and understand how disease and drugs influenced them. Kirkpatrick has been interested in developing methods “to study and understand proteins in rich detail” since his time as a graduate student.

“I think the time has come, where the technologies that we’ve been building for the last two decades are in position to really help us in drug development to give us a unique understanding of the drug targets, of the ways that we should target them, and then ways to read out when we’re successful in doing so—not by looking at a single endpoint, but by looking at the community of proteins and the relationships between them.”

Earlier this year, Sweeney shared his vision with Kirkpatrick and invited him to join Interline. When Kirkpatrick learned who else was advising the startup, “It was really a very easy decision to move over and be a part of this group.”

By the time Kirkpatrick left Genentech, the startup had its founding scientific advisors in place. They include Chodera and Krogan along with:

  • Wade Harper, PhD, chairman and the Bert and Natalie Vallee professor of molecular pathology and cell biology, Harvard Medical School
  • Brenda Schulman, PhD, director, molecular machines and signaling, Max Planck Institute of Biochemistry
  • Mike Varney, PhD, former executive vice president, research and early development,  Genentech

“Basically, in that group, you have the drug development expertise, you have the protein complexes and interactome expertise, and you have the structural biology piece that we will need in order to succeed,” Kirkpatrick said, “It looked to me as though [Sweeney] had assembled effectively the full team that we would need to do exactly what we were envisioning.”

Team building

That team is expected to grow from a dozen or so staffers now, to 15 by mid-year, and to approximately 35 by year’s end.

Joining Sweeney and Kirkpatrick among Interline’s top executives are:

  • Nick Galli, COO and a onetime colleague of Sweeney’s at Genentech and later Denali, where he was vice president of business development
  • Mario Cardozo, PhD, vice president, computational chemistry and cheminformatics, a former scientist at Amgen and MD Anderson Cancer Center
  • Anj Saha, PhD, vice president, discovery pharmacology, whose previous experience includes serving as director, lead discovery at Nurix, where Cardozo was director of computational chemistry
  • David Tully, PhD, vice president, medicinal chemistry, who studied in graduate school with Sweeney before the two later worked together at Novartis to build its infectious disease drug discovery unit when it moved to Emeryville, CA, about a decade ago

Sweeney and partners started building Interline last summer soon after he left Denali Therapeutics, a South San Francisco drug developer where he was founding scientist and chief scientific officer for five years. He joined Foresite Labs, drawn to its incubator model and teams of professionals specializing in genomics and data science, with which Interline continues to interact.

Sweeney took a venture partner position with Foresite Labs and a consulting role with Arch Venture Partners—both of which co-led Interline’s Series A. Interline’s board is chaired by Jim Tananbaum, MD, a co-founder of Foresite Labs and the founder and CEO of Foresite Capital. The company was co-founded last fall and completed its financings in Q1.

“We have a great runway with this financing,” Sweeney said. “According to our current estimates, it should last us at two to three years. But our focus right now is more on building the platform, then reassessing whether or not we’ll be open to additional investment next year.”

Earlier this year, Interline found 6,200 square feet of lab space within Edgewater Business Park in South San Francisco, to where it will move from its current Foresite Labs space. The company plans to start looking for additional expansion opportunities in the second half of this year.

“Even with the limited amount of genetic data that we have, and the limited understanding of protein communities that we’ve been able to glean, we have an improved success rate when our programs are anchored at that intersection,” Sweeney said.

“But we’ve never had the opportunity to really leverage genomics and an understanding of protein communities systematically and prospectively,” Sweeney added. “What I have wanted to do was use that information that’s newly available to find new drugs or common diseases and I thought this was the perfect team to do it with.”