Premium
Discovery of Small Molecules that Induce the Degradation of Huntingtin
Author(s) -
Tomoshige Shusuke,
Nomura Sayaka,
Ohgane Kenji,
Hashimoto Yuichi,
Ishikawa Minoru
Publication year - 2017
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201706529
Subject(s) - huntingtin , ubiquitin , ubiquitin ligase , small molecule , microbiology and biotechnology , proteasome , chemistry , huntingtin protein , mutant , hek 293 cells , dna ligase , biology , biochemistry , receptor , gene
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.