Discovery of Dual BCL-xL/BCL-w Degraders by Exploiting the Bis(sulfonyl)benzene Ring of ABT-263 as a Linkage Vector.

ABSTRACT: Targeting antiapoptotic proteins BCL-xL, BCL-2, and BCL-w has been extensively investigated for cancer treatment. However, robust inhibition of BCL-xL by conventional inhibitors, such as ABT-263, causes thrombocytopenia, a notable drawback that limits the clinical utility of this strategy. To overcome this on-target toxicity, BCL-xL-selective and BCL-xL/BCL-2 dual-targeting proteolysis targeting chimeras (PROTACs) have been developed as alternative therapeutic strategies. In this study, we report a new generation of ABT-263-based PROTACs designed to leverage a novel solvent-exposed region on the bis(sulfonyl)benzene ring of ABT-263, made accessible through regioselective electrophilic aromatic bromination. The lead compounds, 44 and 46, demonstrated effective degradation of B

SUBMITTER: Poddar SK 

PROVIDER: S-EPMC12550731 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature