HYDRACs: Protein-Like Polymers Open New Frontier in Targeted Protein Degradation for Undruggable Cancer Targets
核心洞察
Northwestern University researchers developed HYDRACs (搜索), protein-like polymers that induce proximity-based degradation of notoriously undruggable cancer proteins Myc (搜索) and KRAS (搜索).
Unlike traditional PROTACs or molecular glues, HYDRACs (搜索) use peptide-decorated polymer chains that grab target proteins like "fingers on a hand" and recruit cellular degradation machinery.
The approach addresses the challenge of intrinsically disordered proteins like Myc (搜索), which lack defined binding pockets for small-molecule drugs.
Researchers at Northwestern University have engineered a new class of proximity-inducing molecules—protein-like polymers called HYDRACs (搜索)—that can trigger the degradation of two of cancer's most elusive targets: Myc (搜索) and KRAS (搜索). The work, led by Nathan Gianneschi and published in Nature Communications (2026, DOI: 10.1038/s41467-026-68913-3), introduces a fundamentally different architecture from existing degrader modalities.
A Polymer Solution to a Protein Problem
Myc (搜索) drives many types of cancers, but as an intrinsically disordered protein, it lacks the well-defined binding pockets that small-molecule drugs typically require. KRAS (搜索) presents its own challenges: its smooth surface and shallow topography have earned it a reputation as infamously difficult to drug.
Gianneschi and his team hypothesized that peptides—rather than small molecules—could succeed where conventional approaches have struggled. "Myc (搜索) is a complex, highly disordered protein, but it functions normally in our cells most of the time," Gianneschi said. "Our cells and tissues have no problem with that kind of disorder. It's really human beings looking at disorder and not knowing what to do with it."
The resulting polymers, formally named HYbridDegRAding Copolymers (HYDRACs (搜索)), feature targeting peptides attached along a polymer backbone. These peptide appendages act "like fingers on a hand," grabbing at the targeted proteins, after which the polymers recruit degradation-promoting degrons in the cell to dispose of the proteins.
How HYDRACs (搜索) Fit in the Proximity Medicine Landscape
HYDRACs (搜索) represent a distinct entry in the rapidly evolving field of proximity-inducing therapeutics. Traditional molecular glue degraders function as "double-sided tape," binding an E3 ubiquitin ligase to a target protein and triggering ubiquitination and proteasomal degradation. PROTACs (proteolysis targeting chimeras) achieve similar ends but use a chemical linker with two separate ligands—one for the target protein and one for the E3 ligase.
The first PROTAC to reach the market, Arvinas and Pfizer's vepdegestrant (Veppanu), received FDA approval for advanced breast cancer (搜索), validating the degrader concept. Yet HYDRACs (搜索) differ from both PROTACs and molecular glues by employing a polymeric scaffold rather than a small-molecule framework.
The broader proximity medicine field has attracted substantial investment. AbbVie signed a $1.64 billion deal with Neomorph; Novartis and Monte Rosa Therapeutics penned a $5.7 billion agreement; and Proxygen (搜索) struck a $2.55 billion pact with Merck. Other next-generation modalities include RIPTACs (Regulated Induced Proximity Targeted Chimeras), pioneered by Halda Therapeutics (搜索)—now owned by Johnson & Johnson—which use a "hold and kill" mechanism that binds a target protein to a pan-essential protein required for cell survival, bypassing E3 ligases entirely.
Beyond Degradation: Reprogramming Protein Biology
The field is also expanding beyond simple degradation. Matthias Brand, chief technology officer of Vienna-based Proxygen (搜索), described the broader vision: "One could activate or deactivate specific transcriptional programs by relocalizing transcription factors specifically, create connections between different signaling pathways, change the subcellular localization of proteins and much more."
Proxygen (搜索)'s lead candidates—targeting p300 and CDK12 (搜索)—are expected to enter IND-enabling studies next year. The p300 program features covalent pharmacology designed to deliver durable target degradation even after compound exposure declines, while the CDK12 program exploits the favorable chemical properties of glue degraders to achieve brain penetrance for patients with brain metastases.
Fortitude Biomedicines (搜索) is pursuing yet another angle with its GLUE-DAC technology, which swaps traditional ADC cytotoxic payloads for molecular glue degraders to overcome drug resistance. "Resistance is increasingly emerging as a challenge in the current ADC therapeutic landscape. The field urgently needs payloads with distinct mechanisms of action," said Jin Wang, professor of pharmacology at Baylor College of Medicine.
The Northwestern team's HYDRACs (搜索) add a polymeric dimension to this expanding toolkit, potentially opening a path to targets that have resisted all previous drugging attempts.