Discovery of Small Molecules that Induce the Degradation of Huntingtin

Shusuke Tomoshige, Sayaka Nomura, Kenji Ohgane, Yuichi Hashimoto, Minoru Ishikawa

Research output: Contribution to journalArticlepeer-review

32 Citations (Scopus)

Abstract

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by the aggregation of mutant huntingtin (mHtt), and removal of toxic mHtt is expected to be an effective therapeutic approach. We designed two small hybrid molecules (1 and 2) by linking a ligand for ubiquitin ligase (cellular inhibitor of apoptosis protein 1; cIAP1) with probes for mHtt aggregates, anticipating that these compounds would recruit cIAP1 to mHtt and induce selective degradation by the ubiquitin-proteasome system. The synthesized compounds reduced mHtt levels in HD patient fibroblasts and appear to be promising candidates for the development of a treatment for HD.

Original languageEnglish
Pages (from-to)11530-11533
Number of pages4
JournalAngewandte Chemie - International Edition
Volume56
Issue number38
DOIs
Publication statusPublished - 2017 Sep 11
Externally publishedYes

Keywords

  • Huntington's disease
  • drug design
  • medicinal chemistry
  • protein degradation
  • small-molecule protein degraders

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)

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