# Ubiquitin-independent targeted protein degradation

> **NIH NIH R01** · BRANDEIS UNIVERSITY · 2020 · $741,798

## Abstract

Project Summary
Targeted protein degradation is an exciting new strategy in drug discovery. Such drugs have
several potential advantages: (1) new protein targets must be synthesized to reverse the effect
of the drug, potentially prolonging efficacy; (2) all the domains of the target protein are
inactivated, potentially eliciting different responses than inhibition of a single active site; (3)
each drug molecule can inactivate multiple target molecules, making efficacy event-driven
rather than occupancy-driven, potentially lowering dose and (4) simple binders can be
converted into functional compounds, which may address targets considered “undruggable”.
The rational design of drugs inducing target degradation has almost exclusively focused on a
single over-arching strategy: localization of the target protein to a ubiquitin E3 ligase. The
primary role of ubiquitination is to localize the target protein to the proteasome, and experiments
from several laboratories demonstrate that proteasome localization is sufficient to induce
degradation. These observations suggest a ubiquitin-independent strategy for targeted protein
degradation, wherein a target recognition ligand is linked to a proteasome binding ligand
(proteasome recruiter). Direct localization to the proteasome avoids issues with E3 ligase
localization strategies. Proteasome recruiters also have the potential to be tissue, compartment
and cancer-specific. The goal of this transformative grant is to demonstrate the feasibility of
proteasome recruiters using three strategies: (1) Localization to the 19S regulatory particle; (2)
Localization to a proteasome shuttle factor and (3) localization to the alpha ring of the 20S
proteasome.

## Key facts

- **NIH application ID:** 10021774
- **Project number:** 1R01GM142041-01
- **Recipient organization:** BRANDEIS UNIVERSITY
- **Principal Investigator:** Lizbeth K. Hedstrom
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $741,798
- **Award type:** 1
- **Project period:** 2020-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10021774

## Citation

> US National Institutes of Health, RePORTER application 10021774, Ubiquitin-independent targeted protein degradation (1R01GM142041-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10021774. Licensed CC0.

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