Cancer-driving proteins like MYC and KRAS have long evaded even the most sophisticated drug designs, slipping past small molecules and antibodies that struggle to latch onto their surfaces. Now, researchers at Northwestern University have engineered a new way to eliminate these elusive targets entirely: a protein‑like polymer (PLP) that grabs them and drags them to the cell’s waste‑disposal machinery.
The approach, described in Nature Communications in a paper titled, “Heterobifunctional proteomimetic polymers for targeted degradation of MYC and KRAS,” uses what the team calls HYbrid DegRAding Copolymers, or HYDRACs—a class of proteomimetic polymers designed to mark harmful proteins for destruction rather than merely block their activity. In a proof‑of‑concept study, the researchers deployed HYDRACs against MYC and KRAS, two of the most notorious “undruggable” oncogenic drivers. Both proteins fuel uncontrolled growth in many cancers and, despite decades of effort, have resisted most treatment strategies. The authors wrote, “Existing small-molecule approaches require arduous optimization and are largely confined to targets bearing ligandable pockets.” Their new approach does not require well-defined binding pockets for the PLPs to target.
“MYC and KRAS drive a huge fraction of human cancers—often aggressive ones—and effective drugs for them are extremely limited,” said Northwestern’s Nathan Gianneschi, PhD, who led the study. “We developed a one‑step polymer chemistry solution. The protein mimetic polymers engage disordered proteins and bring them together with the cellular machinery that degrades it.”
HYDRACs work by displaying multiple copies of two components: peptides that recognize the target protein, and peptide-based or small-molecule degrons that recruit the cell’s natural quality‑control system. “Each PLP essentially has two hands,” Gianneschi explained in a press release. “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.”
In cell culture experiments, HYDRACs selectively degraded MYC and KRAS across multiple cancer cell lines. MYC‑targeting HYDRACs shut down MYC‑driven genes and triggered cancer cell death. In mouse models, the polymers accumulated in tumors, reduced proliferation, and stalled tumor growth.
To test the platform’s flexibility, the team reprogrammed HYDRACs to target KRAS, a protein mutated in roughly 25% of human cancers, including pancreatic and colorectal tumors. While recent small‑molecule drugs can hit specific KRAS mutations, cancers often evolve resistance. HYDRACs, by contrast, degraded KRAS proteins carrying multiple alleles. “It doesn’t matter if a protein mutates, it’s still going into the bin,” Gianneschi said. “KRAS can be actively changing, kicking and screaming all the way to the trash can.”
The researchers hope to expand the platform to proteins implicated in neurodegenerative, inflammatory, and metabolic diseases. “By demonstrating this platform with two completely different undruggable proteins, we think it might work to open up other targets,” Gianneschi said. “It’s a new way to think about targeted treatments—not just finding the perfect small molecule…[but] designing systems that work with the cell to eliminate harmful proteins altogether.”
