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

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

  • J Med Chem. 2025 Sep 11;68(17):18684-18702. doi: 10.1021/acs.jmedchem.5c01834.
Saikat K Poddar 1,  Yang Yang 2 3,  Pratik Pal 1,  Zeng Jin 4,  Jing Pei 2 5,  Yufeng Xiao 1,  Wanyi Hu 1,  Peiyi Zhang 1,  Praise Adekunbi 2,  Dinesh Thummuri 5,  Yaxia Yuan 2,  Dongwen Lv 2,  J Peter R Pelletier 4,  Weizhou Zhang 4,  Daohong Zhou 2 5,  Guangrong Zheng 1
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, Florida 32610, United States.
  • 2 Department of Biochemistry and Structural Biology, Center for Innovative Drug Discovery, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, United States.
  • 3 Department of Pharmacology and Therapeutics, College of Medicine, University of Florida, Gainesville, Florida 32610, United States.
  • 4 Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, Florida 32610, United States.
  • 5 Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, Florida 32610, United States.
PMID: 40880408 DOI: 10.1021/acs.jmedchem.5c01834
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 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.

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