TY - JOUR
T1 - Degradation of huntingtin mediated by a hybrid molecule composed of IAP antagonist linked to phenyldiazenyl benzothiazole derivative
AU - Tomoshige, Shusuke
AU - Nomura, Sayaka
AU - Ohgane, Kenji
AU - Hashimoto, Yuichi
AU - Ishikawa, Minoru
N1 - Funding Information:
The work described in this article was partially supported by Grants-in-Aid for Scientific Research from The Ministry of Education, Culture, Sports, Science and Technology, Japan, and the Japan Society for Promotion of Science. GM04281 and GM07492 cells were obtained from the NIGMS Human Genetic Cell Repository at the Coriell Institute for Medical Research.
Funding Information:
The work described in this article was partially supported by Grants-in-Aid for Scientific Research from The Ministry of Education, Culture, Sports, Science and Technology , Japan, and the Japan Society for Promotion of Science . GM04281 and GM07492 cells were obtained from the NIGMS Human Genetic Cell Repository at the Coriell Institute for Medical Research.
Publisher Copyright:
© 2018 Elsevier Ltd
PY - 2018/2/15
Y1 - 2018/2/15
N2 - Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by aggregation of mutant huntingtin (mHtt), and removal of mHtt is expected as a potential therapeutic option. We previously reported protein knockdown of Htt by using hybrid small molecules (Htt degraders) consisting of BE04, a ligand of ubiquitin ligase (E3), linked to probes for protein aggregates. Here, in order to examine the effect of changing the ligand, we synthesized a similar Htt degrader utilizing MV1, an antagonist of the inhibitor of apoptosis protein (IAP) family (a subgroup of ubiquitin E3 ligases), which is expected to have a higher affinity and specificity for IAP, as compared with BE04. The MV1-based hybrid successfully induced interaction between Htt aggregates and IAP, and reduced mHtt levels in living cells. Its mode of action was confirmed to be the same as that of the BE04-based hybrid. However, although the affinity of MV1 for IAP is greater than that of BE04, the efficacy of Htt degradation by the MV1-based molecule was lower, suggesting that linker length between the ligand and probe might be an important determinant of efficacy.
AB - Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by aggregation of mutant huntingtin (mHtt), and removal of mHtt is expected as a potential therapeutic option. We previously reported protein knockdown of Htt by using hybrid small molecules (Htt degraders) consisting of BE04, a ligand of ubiquitin ligase (E3), linked to probes for protein aggregates. Here, in order to examine the effect of changing the ligand, we synthesized a similar Htt degrader utilizing MV1, an antagonist of the inhibitor of apoptosis protein (IAP) family (a subgroup of ubiquitin E3 ligases), which is expected to have a higher affinity and specificity for IAP, as compared with BE04. The MV1-based hybrid successfully induced interaction between Htt aggregates and IAP, and reduced mHtt levels in living cells. Its mode of action was confirmed to be the same as that of the BE04-based hybrid. However, although the affinity of MV1 for IAP is greater than that of BE04, the efficacy of Htt degradation by the MV1-based molecule was lower, suggesting that linker length between the ligand and probe might be an important determinant of efficacy.
KW - Huntington's disease
KW - Inhibitor of apoptosis protein
KW - MV1
KW - Protein knockdown
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U2 - 10.1016/j.bmcl.2018.01.012
DO - 10.1016/j.bmcl.2018.01.012
M3 - Article
C2 - 29366651
AN - SCOPUS:85040650969
SN - 0960-894X
VL - 28
SP - 707
EP - 710
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
IS - 4
ER -