Huntington’s disease (HD) is a fatal neurodegenerative disorder caused by an expanded CAG repeat in the HTT gene, producing mutant huntingtin (mHTT) that misfolds into β-sheet-rich aggregates and drives neuronal loss. Current HTT-lowering strategies face challenges, including invasive delivery and nonselective suppression of wild-type HTT. Here, we report the development and synthesis of proteolysis-targeting chimeras (PROTACs) to selectively degrade aggregated mHTT. The lead compound, PROTAC 2′ , consists of a (pyridylvinyl)aniline aggregate-binding ligand linked via polyethylene glycol spacers to pomalidomide, an E3 ligase recruiter for cereblon. PROTAC 2′ selectively degraded mHTT aggregates without affecting wild-type huntingtin and significantly reduced mHTT-induced cytotoxicity in the cell model. LC–MS/MS analysis confirmed the blood–brain barrier (BBB) penetration ability of PROTAC 2′ following subcutaneous administration. In an R6/2 HD mouse model, continuous PROTAC 2′ delivery via osmotic pumps improved body weight, motor coordination, and survival, correlating with reduced mHTT aggregation and neuroinflammation in the brain. These results highlight the therapeutic potential of aggregate-selective degradation as a disease-modifying strategy for HD, providing a promising alternative to conventional HTT-lowering approaches and supporting the broader potential of PROTAC-based therapeutics for neurodegenerative proteinopathies. This publication is licensed under You are free to share (copy and redistribute) this article in any medium or format and to adapt (remix, transform, and build upon) the material for any purpose, even commercially within the parameters below: Creative Commons (CC): This is a Creative Commons license. Attribution (BY): Credit must be given to the creator. *Disclaimer This summary highlights only some of the key features and terms of the actual license. It is not a license and has no legal value. Carefully review the actual license before using these materials. You are free to share (copy and redistribute) this article in any medium or format and to adapt (remix, transform, and build upon) the material for any purpose, even commercially within the parameters below: Creative Commons (CC): This is a Creative Commons license. Attribution (BY): Credit must be given to the creator. *Disclaimer This summary highlights only some of the key features and terms of the actual license. It is not a license and has no legal value. Carefully review the actual license before using these materials. You are free to share (copy and redistribute) this article in any medium or format and to adapt (remix, transform, and build upon) the material for any purpose, even commercially within the parameters below: Creative Commons (CC): This is a Creative Commons license. Attribution (BY): Credit must be given to the creator. *Disclaimer This summary highlights only some of the key features and terms of the actual license. It is not a license and has no legal value. Carefully review the actual license before using these materials.
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