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

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.