Design, synthesis and evaluation of pyrrolobenzodiazepine (PBD)-based PROTAC conjugates for the selective degradation of the NF-κB RelA/p65 subunit.

ABSTRACT: NF-κB signalling is frequently dysregulated in human cancers making it an attractive therapeutic target. Despite concerted efforts to generate NF-κB inhibitors, direct pharmacological inhibition of the kinases mediating canonical NF-κB has failed due to on-target toxicities in normal tissues. So, alternative strategies, designed to target specific components of the NF-κB signalling machinery, have the potential to selectively inhibit tumour cells whilst reducing the toxicities associated with broad inhibition of NF-κB in non-malignant cells. Here we present evidence that a C8-linked pyrrolobenzodiazepine (PBD) containing proteolysis-targeting chimera (PROTAC) selectively degrades the NF-κB subunit, RelA/p65, in a proteasome-dependent manner. Our lead PROTAC (JP-163-16, 15d) showed cytotoxi

SUBMITTER: Jin P 

PROVIDER: S-EPMC12117510 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature