Heterobifunctional proteomimetic polymers for targeted protein degradation

Area of Science:

• Polymer chemistry
• Chemical biology
• Drug discovery

Background:

• Targeted protein degradation (TPD) offers new ways to target previously undruggable proteins.
• Current TPD methods using small molecules are limited by target accessibility and require extensive optimization.

Purpose of the Study:

• To develop a versatile polymer-based platform, HYbrid DegRAding Copolymer (HYDRAC), for efficient targeted protein degradation.
• To overcome limitations of traditional small-molecule TPD approaches.

Main Methods:

• HYDRACs were synthesized using a modular polymer chemistry approach, displaying peptide or small molecule inducers and target-binding sequences.
• Proof-of-concept studies involved targeting the transcription factor MYC and the KRAS oncoprotein.
• In vivo studies utilized tumor-bearing mice to assess HYDRAC efficacy.

Main Results:

• HYDRACs demonstrated selective degradation of MYC, leading to reduced tumor growth, proliferation, and increased apoptosis in vivo.
• The platform showed versatility by successfully recruiting different E3 ligases (VHL, KEAP1, CRBN) for MYC degradation.
• HYDRACs targeting KRAS achieved degradation in cell lines with different KRAS alleles, suggesting broad applicability.

Conclusions:

• The HYDRAC platform provides a facile, modular, and selective approach for targeted protein degradation.
• HYDRACs show significant therapeutic potential for difficult-to-drug targets like MYC and KRAS.
• This platform expands the therapeutic options within the field of targeted protein degradation.