PXD050659-1

PXD050659 is an original dataset announced via ProteomeXchange.

Title	Heterobifunctional proteomimetic polymers for targeted protein degradation
Description	The burgeoning field of targeted protein degradation (TPD) has opened new avenues for modulating the activity of previously undruggable proteins of interest. To date, TPD has been dominated by small molecules containing separate linked domains for protein engagement and recruitment of cellular degradation machinery. The process of identifying active compounds has required tedious optimization and has been successful largely against a limited set of targets with well-defined, suitable docking pockets. Here we present a polymer chemistry approach termed the HYbrid DegRAding Copolymer (HYDRAC) to overcome standing challenges associated with the development of TPD. These copolymers densely display either peptide-based or small molecule-derived degradation inducers and target-binding peptide sequences for the selective degradation of disease-associated proteins. HYDRACs are synthesized in a facile manner, are modular in design, and are highly selective. Using the intrinsically disordered transcription factor MYC as an initial proof-of-concept, difficult to drug protein target, HYDRACs containing a MYC-inhibitory peptide copolymerized with a validated degron, showed robust and selective degradation of the target protein. Treatment of tumor-bearing mice with MYC-targeted HYDRACs showed decreased cell proliferation and increased tumor apoptosis, leading to significantly suppressed tumor growth in vivo. The versatility of the platform was demonstrated by substituting the degron for recruiters of three different E3 ligases (VHL, KEAP1, and CRBN), which all maintained MYC degradation. To demonstrate generalizability, HYDRACs were further designed against a second elusive target of clinical interest, KRAS, by employing a consensus RAS binding motif. RAS-targeted HYDRACs showed degradation in two cell lines harboring separate KRAS alleles, suggesting potential pan-KRAS activity. We envision the HYDRAC platform as a generalizable approach to developing degraders of proteins of interest, greatly expanding the therapeutic armamentarium for TPD.
HostingRepository	PRIDE
AnnounceDate	2026-01-28
AnnouncementXML	Submission_2026-01-28_05:26:38.946.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Xiaoyu Zhang
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	iodoacetamide derivatized residue
Instrument	Orbitrap Eclipse

Revision	Datetime	Status	ChangeLog Entry
0	2024-03-15 08:23:34	ID requested
⏵ 1	2026-01-28 05:26:39	announced

10.1038/S41467-026-68913-3;

submitter keyword: targeted protein degradation

Xiaoyu Zhang
contact affiliation	Northwestern University, Department of Chemistry
contact email	zhang@northwestern.edu
lab head
Xiaoyu Zhang
contact affiliation	Northwestern University
contact email	zhang@northwestern.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD050659
     1. Label: PRIDE project
     2. Name: Heterobifunctional proteomimetic polymers for targeted protein degradation