Structure–Activity–Property Relationships of MZ1-Based Trivalent PROTACs Incorporating a 1,2,5-Trisubstituted Benzene Linker

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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Publication Details

Journal
Chemical and Pharmaceutical Bulletin
Published
2026-07-27
DOI
https://doi.org/10.1248/cpb.c26-00126
Primary Topic
Protein Degradation and Inhibitors
Type
article
Field-Weighted Citation Impact
0.00

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article

Structure–Activity–Property Relationships of MZ1-Based Trivalent PROTACs Incorporating a 1,2,5-Trisubstituted Benzene Linker

Naoki Kanoh, Kazuto Nunomura, Fumiaki Ohtake, Yumi Shiozaki-Sato et al.
Chemical and Pharmaceutical Bulletin
Protein Degradation and Inhibitors
article

Structure–Activity–Property Relationships of MZ1-Based Trivalent PROTACs Incorporating a 1,2,5-Trisubstituted Benzene Linker

Naoki Kanoh, Kazuto Nunomura, Fumiaki Ohtake, Yumi Shiozaki-Sato, Junko Fujimoto, Makoto Kawatani, Kazutada Ikeuchi, Hiromasa Yokoe, Hiroaki Saito, Bangzhong Lin, Hiroshi Morita, Toshio Kaneda, Yifan Huang, Mai Murata, Hiroyuki Osada
article en

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.

Chemical and Pharmaceutical BulletinVol. 74(7)
Hoshi University (JP), RIKEN Center for Sustainable Resource Science (JP), Microbial Chemistry Research Foundation (JP), Hokuriku University (JP), Ebara (Japan) (JP), The University of Osaka (JP)
Japan Agency for Medical Research and Development, Royal College of Surgeons in Ireland, Promotion and Mutual Aid Corporation for Private Schools of Japan, Japan Society for the Promotion of Science
Zero hunger
Openalex Percentile: Top 15%
Protein Degradation and Inhibitors
DOIOpen Access PDFOpenAlex
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