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, <b>44</b> and <b>46</b>, 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.
Authors
- Saikat Kumar Poddar (ORCID: https://orcid.org/0000-0003-2317-0996)
- Wanyi Hu
- Pratik Pal (ORCID: https://orcid.org/0009-0003-2763-0096)
- Yufeng Xiao (ORCID: https://orcid.org/0000-0002-2679-0800)
- Weizhou Zhang (ORCID: https://orcid.org/0000-0002-8236-0346)
- Jin Zeng (ORCID: https://orcid.org/0000-0002-0872-587X)
- Yaxia Yuan (ORCID: https://orcid.org/0000-0001-7094-4419)
- Dinesh Thummuri (ORCID: https://orcid.org/0000-0002-6027-0999)
- Guangrong Zheng (ORCID: https://orcid.org/0000-0002-8106-6663)
- J. Peter R. Pelletier (ORCID: https://orcid.org/0000-0002-2320-3180)
- Yang Yang (ORCID: https://orcid.org/0000-0003-0428-5480)
- Pengfei Zhang (ORCID: https://orcid.org/0000-0003-3470-085X)
- Daohong Zhou (ORCID: https://orcid.org/0000-0002-2400-6461)
- Jing Pei (ORCID: https://orcid.org/0009-0000-8683-3449)
- Dongwen Lv (ORCID: https://orcid.org/0009-0005-5073-0313)
- Praise Adekunbi
Institutions
- The University of Texas at San Antonio Health Science Center (US)
- University of Florida (US)
- Drug Discovery Laboratory (Norway) (NO)
- Medicina (PL)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-08-29
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c01834
- Citations
- 1
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 0.81
Funders
- National Cancer Institute