TY - JOUR
T1 - Conversion of a PROTAC Mutant Huntingtin Degrader into Small-Molecule Hydrophobic Tags Focusing on Drug-like Properties
AU - Hirai, Keigo
AU - Yamashita, Hiroko
AU - Tomoshige, Shusuke
AU - Mishima, Yugo
AU - Niwa, Tatsuya
AU - Ohgane, Kenji
AU - Ishii, Mayumi
AU - Kanamitsu, Kayoko
AU - Ikemi, Yui
AU - Nakagawa, Shinsaku
AU - Taguchi, Hideki
AU - Sato, Shinichi
AU - Hashimoto, Yuichi
AU - Ishikawa, Minoru
N1 - Funding Information:
The work described in this Letter was partially supported by the Japan Society for the Promotion of Science (JSPS KAKENHI Grant Number JP19K16326, S.T.; 18H02551 and 18H05502, M.I.), Japan Science and Technology Agency (JST ACT-X Grant number JPMJAX2018, S.T.), The Uehara Memorial Foundation (201920310, M.I.), and AMED-CREST, AMED (JP21gm1410007, M.I.). The cells GM04281 and DNA sample CH00019 were obtained from the NIGMS Human Genetic Cell Repository at the Coriell Institute for Medical Research. Caco-2 permeability assay was carried out by Eurofins Discovery. In vivo brain permeability analysis was supported by AMED-BINDS program (JP21am0101087, JP21am0101123, 3198).
Publisher Copyright:
© 2022 American Chemical Society
PY - 2022/3/10
Y1 - 2022/3/10
N2 - 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.
AB - 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.
KW - PROTACs
KW - drug-like properties
KW - hydrophobic tagging
KW - neurodegenerative disorders
KW - protein degradation
UR - http://www.scopus.com/inward/record.url?scp=85125405382&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85125405382&partnerID=8YFLogxK
U2 - 10.1021/acsmedchemlett.1c00500
DO - 10.1021/acsmedchemlett.1c00500
M3 - Article
AN - SCOPUS:85125405382
SN - 1948-5875
VL - 13
SP - 396
EP - 402
JO - ACS Medicinal Chemistry Letters
JF - ACS Medicinal Chemistry Letters
IS - 3
ER -