Polymer Degraders Destroy Undruggable MYC and KRAS Cancer Proteins in Mice

The protein MYC drives uncontrolled proliferation in cancers of the breast, colon, lung, prostate, liver, blood, and ovaries. KRAS does the same in about 25 percent of all human cancers, with a particularly strong presence in pancreatic and colorectal tumors. Together, they represent two of the most consequential drivers of cancer mortality. They are also among the most stubbornly resistant to drugs - so much so that the field coined a specific term for proteins like them: undruggable.

The label is not arbitrary. Conventional small-molecule drugs work by fitting into specific grooves and pockets on a protein's surface, blocking its activity. MYC and KRAS lack well-defined binding pockets. Their surfaces are disordered and flexible in ways that prevent small molecules from latching on with sufficient force. Decades of drug development effort have produced limited options - KRAS inhibitors targeting one specific mutation exist but lose effectiveness as cancers develop resistance, and MYC inhibitors remain elusive for most tumor types.

Taking a different approach entirely

A study published in Nature Communications from Nathan Gianneschi's group at Northwestern University proposes that the binding-pocket problem is worth circumventing rather than solving. Instead of trying to block these proteins, the Northwestern team designed polymers that grab them and hand them to the cell's own waste-disposal system for destruction.

The approach builds on targeted protein degradation, a broader therapeutic concept that has gained significant momentum in recent years. Existing degraders typically use small molecules - called PROTACs - that link a target protein to an E3 ubiquitin ligase, which then tags the protein for proteasomal degradation. The problem is that PROTACs still require a small-molecule component that must bind the target protein, which circles back to the binding-pocket problem for undruggable proteins.

Gianneschi's team developed protein-like polymers (PLPs) called HYDRACs - HYbrid DegRAding Copolymers. Each HYDRAC carries multiple copies of two types of functional groups: peptides that recognize and bind the target protein (exploiting weaker, distributed interactions rather than needing one perfect pocket), and molecular signals that attract the cell's degradation machinery. The polymer essentially has two gripping ends.

"Each PLP essentially has two hands," Gianneschi said. "One hand grabs the protein, and the other hand grabs the cell's 'dust bin.' It's literally like picking up a piece of trash off the ground, grabbing the waste basket and putting them near each other."

Results in cells and mice

In cancer cell cultures, MYC-targeted HYDRACs selectively degraded MYC protein, shut down MYC-driven gene expression, and triggered cancer cell death. The team then moved to a mouse model carrying MYC-driven tumors. MYC-targeted HYDRACs accumulated in tumors after administration, reduced cancer cell proliferation, and stalled tumor growth. No significant side effects were observed at the doses tested.

To test whether the platform was adaptable rather than a one-protein solution, the team reprogrammed HYDRACs to target KRAS. The modified polymers selectively degraded KRAS proteins in cancer cells - including proteins carrying different KRAS mutations, which has been a persistent limitation of existing KRAS-specific small-molecule drugs.

"In many cases, patients became resistant to the drugs as the cancer mutates to resist treatment," Gianneschi noted about current KRAS inhibitors. "KRAS can be actively changing, kicking and screaming all the way to the trash can, but all we need to do is destroy the whole protein. This is a potentially powerful way to foil the cell which cannot easily mutate away from your drug."

What the mouse data cannot establish

Animal tumor models, while essential screening tools, have a poor track record as predictors of human clinical success. Many compounds that eliminate tumors in mice fail in human trials due to differences in drug metabolism, immune response, pharmacokinetics, and tumor heterogeneity. MYC-driven tumor models in mice may not capture the complexity of human MYC-expressing cancers, which vary widely by tissue type and genetic background.

The HYDRAC platform has not been tested in humans. Questions of dosing, delivery, biodistribution, long-term toxicity, and manufacturing at clinical scale remain uncharacterized. The polymers must reach tumor cells in adequate concentrations without causing harm to healthy tissues - a challenge that has complicated many polymer-based drug delivery systems.

Gianneschi's group plans to adapt HYDRACs to proteins involved in neurodegenerative, inflammatory, and metabolic diseases. Northwestern spinout Grove Biopharma has licensed the technology and is developing it as part of its Bionic Biologics platform.

The study was supported by the Willens Center for Nano Oncology, the International Institute of Nanotechnology, and the Liz and Eric Lefkofsky Innovation Research Award.