Structure–Activity–Property Relationships of MZ1-Based Trivalent PROTACs Incorporating a 1,2,5-Trisubstituted Benzene Linker
Abstract
Studies on the structure-activity-property relationships of MZ1-based trivalent proteolysis-targeting chimeras (PROTACs) incorporating a trisubstituted benzene linker, particularly the 1,2,5-trisubstituted type, were conducted with a focus on the linker and the functional group introduced at the 5-position on the benzene ring. Introducing a polar, charged functional group at the end of the linker significantly increased the PROTAC's solubility. However, this polar group also significantly impaired the Brd4 degradation-inducing activity of these PROTACs, even though the PROTACs were designed not to disrupt the ternary complex formation among the POI, the E3 ligase, and the PROTAC. Capping the polar functional group restored the activity. These findings will be useful for designing functional PROTACs and PROTAC-based probes and will also help elucidate the modes of action of PROTACs.
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BibTeX
@article{huang2026structureactivityproperty,
title = {{Structure–Activity–Property Relationships of MZ1-Based Trivalent PROTACs Incorporating a 1,2,5-Trisubstituted Benzene Linker}},
author = {Yifan Huang and Toshio Kaneda and Mai Murata and Hiroshi Morita and Bangzhong Lin and Kazuto Nunomura and Hiroaki Saito and Yumi Shiozaki-Sato and Makoto Kawatani and Hiroyuki Osada and Fumiaki Ohtake and Junko Fujimoto and Hiromasa Yokoe and Kazutada Ikeuchi and Naoki Kanoh},
journal = {Chemical and Pharmaceutical Bulletin},
year = {2026},
month = jul,
doi = {10.1248/cpb.c26-00126},
url = {https://www.jstage.jst.go.jp/article/cpb/74/7/74_c26-00126/_article},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Structure–Activity–Property Relationships of MZ1-Based Trivalent PROTACs Incorporating a 1,2,5-Trisubstituted Benzene Linker
AU - Yifan Huang
AU - Toshio Kaneda
AU - Mai Murata
AU - Hiroshi Morita
AU - Bangzhong Lin
AU - Kazuto Nunomura
AU - Hiroaki Saito
AU - Yumi Shiozaki-Sato
AU - Makoto Kawatani
AU - Hiroyuki Osada
AU - Fumiaki Ohtake
AU - Junko Fujimoto
AU - Hiromasa Yokoe
AU - Kazutada Ikeuchi
AU - Naoki Kanoh
PY - 2026
DA - 2026/07/28
JO - Chemical and Pharmaceutical Bulletin
DO - 10.1248/cpb.c26-00126
UR - https://www.jstage.jst.go.jp/article/cpb/74/7/74_c26-00126/_article
AB - Studies on the structure-activity-property relationships of MZ1-based trivalent proteolysis-targeting chimeras (PROTACs) incorporating a trisubstituted benzene linker, particularly the 1,2,5-trisubstituted type, were conducted with a focus on the linker and the functional group introduced at the 5-position on the benzene ring. Introducing a polar, charged functional group at the end of the linker significantly increased the PROTAC's solubility. However, this polar group also significantly impaired the Brd4 degradation-inducing activity of these PROTACs, even though the PROTACs were designed not to disrupt the ternary complex formation among the POI, the E3 ligase, and the PROTAC. Capping the polar functional group restored the activity. These findings will be useful for designing functional PROTACs and PROTAC-based probes and will also help elucidate the modes of action of PROTACs.
SN - 1347-5223
SN - 0009-2363
ER -