Conversion of a PROTAC Mutant Huntingtin Degrader into Small-Molecule Hydrophobic Tags Focusing on Drug-like Properties

Keigo Hirai, Hiroko Yamashita, Shusuke Tomoshige, Yugo Mishima, Tatsuya Niwa, Kenji Ohgane, Mayumi Ishii, Kayoko Kanamitsu, Yui Ikemi, Shinsaku Nakagawa, Hideki Taguchi, Shinichi Sato, Yuichi Hashimoto, Minoru Ishikawa

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)


The onset of neurodegenerative disorders (NDs), such as Alzheimer’s disease, is associated with the accumulation of aggregates of misfolded proteins. We previously showed that chemical knockdown of ND-related aggregation-prone proteins can be achieved by proteolysis targeting chimeras (PROTACs). However, hetero-bifunctional PROTACs generally show poor permeability into the central nervous system, where NDs are located. Here, we document the conversion of one of our PROTACs into hydrophobic tags (HyTs), another class of degraders bearing hydrophobic degrons. This conversion decreases the molecular weight and the number of hydrogen bond donors/acceptors. All the developed HyTs lowered the level of mutant huntingtin, an aggregation-prone protein, with potency comparable to that of the parent PROTAC. Through IAM chromatography analysis and in vivo brain penetration assay of the HyTs, we discovered a brain-permeable HyT. Our results and mechanistic analysis indicate that conversion of protein degraders into HyTs could be a useful approach to improve their drug-like properties.

Original languageEnglish
Pages (from-to)396-402
Number of pages7
JournalACS Medicinal Chemistry Letters
Issue number3
Publication statusPublished - 2022 Mar 10


  • drug-like properties
  • hydrophobic tagging
  • neurodegenerative disorders
  • protein degradation

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry


Dive into the research topics of 'Conversion of a PROTAC Mutant Huntingtin Degrader into Small-Molecule Hydrophobic Tags Focusing on Drug-like Properties'. Together they form a unique fingerprint.

Cite this