Broaden the Druggable Proteome with Intracellular Goal Engagement

Many biologically compelling proteins are deprioritized because they cannot be easily assayed in cells, creating a disconnect between biochemical discovery and physiological relevance. Debuted at the Society for Laboratory Automation and Screening (SLAS) International Conference and Exhibition on February 10, 2026, Promega’s TarSeer™ BRETSA™ Target Engagement System seeks to bridge that divide. The platform applies a BRET-based method to monitor protein denaturation and stabilization in real time within living cells, enabling detection of ligand–protein interactions.

In this Innovation Spotlight, Matthew Robers, the associate director of Research and Development at Promega, discusses the challenges facing drug discovery involving “non-assayable” proteins and highlights how this new platform broadens the range of targets accessible to early-stage drug discovery.

Why do scientists abandon certain promising drug targets?

There are many reasons why a drug discovery effort can get derailed for a given protein target. We focus on challenges from the assay technology standpoint, and we like to think about the questions of tractability. When pharma companies select a protein target to build an entire program around, they prioritize targets based on a tractability assessment. Are there tool molecules developed for this target? How assayable is it? Does it have a well-described function that we can interrogate and modulate in a way that leads to a desired therapeutic outcome? There is a process to de-risking when selecting a target and before making a major investment.

We like to focus on “no assay” targets—proteins that can’t be purified or don’t have a well-described function. Maybe they don’t have a binding pocket for a metabolite that can be mimicked with a drug-like molecule. A lot of protein targets get abandoned or deprioritized because they don’t check all those boxes: Do I have an assay? Do I have a function? Do I have a compound? Do I have the right tools in the toolbox to create a therapeutic?

Unfortunately for most human proteins, we don’t have all those boxes checked. So, during this tractability assessment, the community often throws out potentially interesting proteins. They either don’t interrogate them or, if the protein cannot be studied in its native environment, a modified version of that protein is created through mutagenesis or truncation. They might make a smaller domain that behaves better experimentally and hope it serves as a proxy for the full-length protein inside a human cell. But by artificializing that protein, they may create something that doesn’t truly represent the authentic disease-driving protein. They then develop molecules that bind to or modulate that artificial version, and those molecules may not behave the same way in diseased tissue. I see the process being derailed at that de-risking step—either by people abandoning targets because they don’t check all the boxes, or by studying mutated versions that no longer reflect the authentic protein.

What Promega does is ask, “What methods or technologies could change how the community prioritizes drug targets? Could we provide a tool that makes a non-assayable protein assayable—without artificializing it or abandoning it altogether?”

What improvements are needed in target engagement assays for drug development, and how does Promega intend to expand the druggable proteome?

We are thinking about how biophysics can be used to understand drug target engagement. There are decades of research behind different biophysical methods, but many of them have been limited to purified protein analysis. Promega’s philosophy has always been about taking biochemical methods and making them work inside living cells. That’s where we laser-focus: How can we bring a biochemical method into the cell?

Our technology allows researchers to get the precision, robustness, sensitivity, and high-throughput screening capability of a biochemical assay, but in the environment of a living cell, where those tools traditionally haven’t worked. It’s about marrying scalability and sensitivity with accurate, physiologically relevant conditions. That’s where we love to create new chemistries.

How does your new platform work, and what are the main advantages of this system?

The TarSeer™ BRETSA™ Target Engagement System is based on a biophysical principle: protein denaturation. This is a decades-old concept that scientists have used to understand protein unfolding and to measure small-molecule binding. When you heat a protein, it unfolds. Residues that are normally buried within the 3D structure, especially hydrophobic residues, become exposed, and eventually the protein aggregates, phase-separates, and falls out of solution.

For many years, researchers have known that small-molecule binding can energetically stabilize a protein against this denaturation and aggregation process. But this has almost exclusively been measured in cell-free systems using purified protein. Promega created a way to observe that denaturation process in real time in living cells through resonance energy transfer. In this case it is bioluminescence resonance energy transfer (BRET), and our version of that method is called NanoBRET.

With this new method, we can measure protein unfolding in a living cell and demonstrate that drug binding energetically stabilizes the protein against denaturation. We can do all of that in a high-throughput format. This has the potential to accelerate drug development and facilitate the identification of novel chemical entities that bind to a protein target.

Did your scientists have to overcome any challenges to develop this platform?

Yes, there was a major challenge. There are organic dyes that detect protein unfolding and denaturation. They’ve been used in biochemical assays for decades and are real workhorse reagents. We tried to use those commercially available dyes in our assay, and they simply didn’t work. So, we had to go back to the drawing board.

Fortunately, we have a group of very tenacious chemists at Promega who specialize in creating novel dyes for novel applications. They developed a new series of probes that can enter living cells and detect proteins as they unfold in real time. Overcoming the limitations of the dye chemistry, and finding one that works inside living cells, was not trivial. That was a significant technical hurdle for us.

What feedback have you received from researchers who have tested the platform?

We’ve initiated collaborations ahead of our commercialization with academic and industry drug hunters. They’ve started incorporating the BRET shift assay, or BRETSA™, into their workflows. The feedback so far has been very positive. By and large, they’re seeing that this is a more sensitive method than existing approaches for measuring target engagement through protein denaturation.

It’s extremely sensitive, which means it can detect weak-affinity interactions, but it can also resolve very high-affinity interactions. It provides a sensitive and accurate way to understand drug binding and even extract potency data in a way that’s quite different from what’s been done previously.

How will this new platform change the drug discovery landscape?

Our hope—and we haven’t proven this yet—is that it salvages drug targets that would otherwise never be pursued. Or, if they were pursued, they might only be studied in an artificial way. We hope this provides a lever that allows researchers to bring lesser-studied proteins into the mix as viable drug targets, rather than putting them on the shelf simply because there wasn’t a good tool to interrogate them.