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

2026/07/27 by Yifan Huang, Toshio Kaneda, Mai Murata +12
Biochemistry, Genetics and Molecular Biology · Chemistry · #Chromatin Remodeling and Cancer #Click Chemistry and Applications #Protein Degradation and Inhibitors

paper · pdf · doi:10.1248/cpb.c26-00126

openalex publication_date 2026/07/27 · crossref created 2026/07/27 · crossref issued 2026/07/28 · crossref published 2026/07/28 · crossref published-print 2026/07/28 · openalex created_date 2026/07/28 · openalex updated_date 2026/07/31 · crossref deposited 2026/08/01 · crossref indexed 2026/08/01

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.