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

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 BCL-xL and, unexpectedly,
degraded BCL-w, while sparing BCL-2. With further optimization, these
BCL-xL and BCL-w dual-targeting PROTACs hold great promise as safer,
more effective anticancer agents against BCL-xL and BCL-w codependent
cancers.