Stapled Peptide-Degron Chimeras A Dana-Farber Approach to Targeted Protein Degradation

This patent describes a class of chimeric molecules that locate a chosen disease-driving protein inside a cell and then recruit the cell’s own protein-destruction machinery to eliminate it. The approach combines two structural elements into a single compound: a stapled peptide that locks onto the target, and a degron that flags it for disposal.

The Problem

A long-standing challenge in drug discovery is that many of the most important disease-driving proteins are considered “undruggable” by conventional small molecules. Transcription factors, scaffolding proteins, and mutant oncogenes such as KRAS, MYC and the BCL2 family lack the deep, shaped binding pockets that small molecules exploit to shut down enzymes like kinases or proteases. Short natural peptides can recognise these targets, but they degrade quickly in cells and rarely survive the journey to their target intact.

Even when binders can be found, occupying a target is not the same as removing it. Proteins accumulate, diffuse, and reform complexes. Blocking a single active site often leaves other pathological interactions intact. Cellular protein-degradation pathways – particularly the ubiquitin-proteasome system – offer a more definitive answer, because a tagged protein is physically destroyed rather than merely inhibited. Accessing these pathways in a programmable way has been one of the most active areas of oncology research over the past decade.

What This Invention Does

The invention is a chimeric molecule built from two halves that perform complementary jobs. One half is a stapled peptide: a short peptide whose shape has been locked in place by a covalent hydrocarbon bridge (or equivalent staple chemistry), giving it the stability of a small molecule with the reach and specificity of a protein loop. The other half is a degron: a chemical handle that the cell’s E3 ubiquitin ligases recognise, such as a thalidomide-derived moiety that binds cereblon (CRBN) or a VHL-binding fragment.

When the combined molecule enters a cell, the peptide half seeks out and binds its chosen disease protein, while the degron half recruits an E3 ligase. The ligase transfers ubiquitin onto the captured target, marking it for the proteasome. The target is then broken down by the cell’s normal degradation pipeline, and the chimeric molecule is free to find another copy of the target and repeat the cycle. The patent describes four structural variants of the scaffold, covering stapled-peptide-plus-small-molecule-degron, stapled-peptide-plus-peptide-degron, stapled-peptide-degron pairs, and inverted arrangements.

Key Features

• Stapled peptide targeting arm. Hydrocarbon stapling (or alternative chemical crosslinks) locks the peptide into its active alpha-helical shape, dramatically improving stability, cell permeability, and binding affinity compared to natural peptides.
• Flexible degron choice. The destruction arm can be a small-molecule E3 recruiter (cereblon-binders such as thalidomide derivatives, VHL-binding ligands) or a peptide degron sequence – giving medicinal chemists multiple chemistry paths to optimise each asset.
• Broad target spectrum. The disclosed scope explicitly includes the BCL2 apoptosis family, MYC, KRAS/NRAS/HRAS, EZH2, HDM2/HDMX, beta-catenin, PI3K, PTEN, AKT, receptor tyrosine kinases, PD-1 and more – most of which have historically resisted small-molecule approaches.
• Catalytic degradation mode. Because the chimera triggers destruction rather than occupying the target, a single molecule can process many copies of the target protein, potentially offering higher pharmacological efficiency than conventional inhibitors.
• Beyond human disease. The filings extend to stapled peptides that bind bacterial and viral proteins, pointing toward applications in infectious disease alongside the oncology-focused core.

Who Is Behind It?

The applicant is Dana-Farber Cancer Institute, one of the most prominent cancer research hospitals in the United States. The inventor list reads as a cross-section of the institute’s leadership in targeted protein degradation and peptide chemistry: Rida Mourtada, Henry D. Herce, Loren D. Walensky, Gregory H. Bird, Ann Maurine Morgan, and James E. Bradner – with Bradner in particular a well-known figure in the early development of protein-degradation therapeutics. The Australian application is a divisional of 2024200512 and traces back to US provisional filing 62/599,608 from December 2017. The Australian patent agent is Wrays Pty Ltd in Perth.

Why It Matters

Targeted protein degradation has become one of the most closely watched modalities in oncology, with small-molecule PROTACs and molecular glues already in late-stage clinical trials. The stapled-peptide approach described here extends that toolkit to an entirely different class of targets – the proteins whose surfaces are too smooth or shallow for traditional small molecules to grip. If the peptide-degron chimeras progress through preclinical and clinical testing, they could open therapeutic access to some of the longest-standing unmet needs in cancer treatment, including mutant KRAS and MYC, alongside further applications in immunology and anti-infectives. The Australian filing is part of a multi-jurisdictional family that also covers the technology in the United States, Europe and elsewhere.

AU 2026201801 was published in the Australian Official Journal of Patents on 2 April 2026 and is open for public inspection. Patent applications represent inventions that are sought to be protected and do not necessarily reflect commercially available products.