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Interline Therapeutics Taking Protein Interaction-Based Approach to Drug Development

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NEW YORK – Pharma startup Interline Therapeutics is betting that advances in omics technologies can make for more effective drug development programs.

The South San Francisco-based company, which launched Thursday with $93 million in funding from Foresite Capital and ARCH Ventures, looks to explore how disease-linked genetic variants alter protein interaction networks to identify drug targets and drugs to address inflammatory diseases and cancer.

Key to its approach is the use of mass spectrometry-based proteomics to characterize protein interaction networks of interest and follow how they are altered in particular disease states and can potentially be manipulated via therapeutic agents.

"The focus of Interline will be protein community-based drug development," said Don Kirkpatrick, Interline's vice president and CTO. Kirkpatrick was previously a staff scientist and director at Genentech where he specialized in mass spectrometry-based proteomics.

He noted that the large and growing number of sequenced human genomes available provides scientists with an unparalleled opportunity to understand disease at the genetic level, but that to effectively translate those genetic insights into protein drug targets requires a better understanding of proteins as they actually exist in the body, meaning as part of networks and communities of interaction.

"The challenge comes when you start to think about individual proteins as drug targets, because so often the drug targets live in this rich and complex dynamic protein community where its levels, its activity, its interactions are really influenced by so many of the other proteins that are in that community with them," Kirkpatrick said.

"The thought here is that we have reached a point technologically where we can step away from thinking about just a single drug target and really try to understand all the relationships between the different proteins that are part of that community systematically and early on as part of our drug-development process," he added.

Interline CEO Zach Sweeney, who was previously chief scientific officer at Denali Therapeutics, cited as an example the protein TYK2, which is involved in the body's cytokine response. A protective variant of the protein has reduced association with cytokine receptors and has been shown to be protective against various inflammatory conditions, though it enhances risk of some infectious diseases like tuberculosis.

A number of drugs currently in development for inflammatory conditions "essentially directly mimic the effect of this variant by reducing the association of TYK2 with cytokine receptors," Sweeney said.

"That kind of outlines the principles of our platform, where we start with genetic variation, prioritize variants that are affecting protein community interactions and direct protein associations, and use this insight… to identify molecules that mimic [or inhibit] the effect of these variants on protein communities," he said.

Sweeney and Kirkpatrick noted that a number of technological advances have come together in recent years that make such an approach attractive. First, there is the wealth of genomic data that makes it possible to identify disease linked variants. In addition, advances in cell line technologies have expanded the range of cell types researchers can easily work with, while the emergence of approaches like CRISPR allow scientists to more easily produce the variant genes of interest in those cell lines.

Finally, improvements in mass spec technology allow researchers to better track protein-protein interactions across large numbers of experimental conditions and time points, giving them a broader and higher-resolution look at how genetic variants and/or therapeutic agents reshape protein interaction networks.

Kirkpatrick said that the company typically starts with pull-down experiments, pulling out tagged proteins and using mass spec to look at what other proteins are interacting with them, and collecting quantitative data on those proteins across multiple time points to understand the baseline dynamics of their interactions.

"Then from there you can imagine bringing in variants and small-molecule modulators that would allow us to then either stabilize or destabilize specific interactions and look at how the consequences of that play out across the community," he said.

As an example of the company's protein interactome analyses work, Kirkpatrick cited collaborative research with the University of California, San Francisco on irritable bowel disease.

He noted that the researchers will be interrogating more than 50 proteins in detail, initially defining their interactions in a model organism, then examining them on the scale of minutes to hours to better understand what their dynamics look like in a typical signaling time frame.

Kirkpatrick highlighted isobaric labeling tools like TMT reagents and improvements in mass spec performance as keys to the approach.

"You can really move through samples quickly … with really complex lists of features that you want to analyze," he said. "It's possible to make methods systematically where one can run through essentially 100-plex assays on a timescale were you can really characterize many, many different conditions."

Kirkpatrick said Interline is also interested in exploring non-mass spec proteomics technologies from companies like Swedish proteomics outfit Olink; emerging technologies from firms like Seattle-based proteomics startup Nautilus; and spatial proteomics tools from firms like Menlo Park, California-based IonPath.

Interline is one of several young drug development firms looking to leverage new protein analysis technologies. Last week, Hayward, California-based Eikon Therapeutics, which was founded in 2019, announced it closed a $148 million Series A financing round led by Column Group with participation from Interline-backer Foresite Capital, as well as Innovation Endeavors and Lux Capital.

The company, which also announced it had appointed as CEO Roger Perlmutter, the former president of Merck Research Laboratories, uses a super-resolution microscopy-based platform to track the movement and behavior of proteins in live cells in a high-throughput manner.

Also last week, Sunnyvale, California-based BridGene Biosciences, which launched in 2018, announced the close of a $12 million Series A found led by Wedo Venture Partners with participation from Kaitai Capital, Takede Ventures, and Pangu Venture. The company's IMTAC (Isobaric Mass Tagged Affinity Characterization) uses mass spec to quantify the binding of ligands to proteins proteome-wide, allowing researchers to collect detailed information on ligand-protein binding affinity and selectivity.

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