Discovery of XZ338, a highly potent BCL-XL degrader

  • Eur J Med Chem. 2025 Jul 5:291:117624. doi: 10.1016/j.ejmech.2025.117624.
Xuan Zhang  1 ,  Dinesh Thummuri  2 ,  Wanyi Hu  1 ,  Xingui Liu  3 ,  Peiyi Zhang  1 ,  Shuo Zhou  4 ,  Daohong Zhou  5 ,  Guangrong Zheng  6
Affiliations
  • 1. Department of Medicinal Chemistry and College of Pharmacy, University of Florida, 1333 Center Drive, Gainesville, FL, 32610, United States.
  • 2. Department of Pharmacodynamics, College of Pharmacy, University of Florida, 1333 Center Drive, Gainesville, FL, 32610, United States.
  • 3. Department of Medicinal Chemistry and College of Pharmacy, University of Florida, 1333 Center Drive, Gainesville, FL, 32610, United States; Department of Pharmacodynamics, College of Pharmacy, University of Florida, 1333 Center Drive, Gainesville, FL, 32610, United States.
  • 4. Department of Pharmacodynamics, College of Pharmacy, University of Florida, 1333 Center Drive, Gainesville, FL, 32610, United States; Department of Biochemistry and Structure Biology, Center of Innovative Drug Discovery, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, United States.
  • 5. Department of Pharmacodynamics, College of Pharmacy, University of Florida, 1333 Center Drive, Gainesville, FL, 32610, United States; Department of Biochemistry and Structure Biology, Center of Innovative Drug Discovery, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, United States. Electronic address: [email protected].
  • 6. Department of Medicinal Chemistry and College of Pharmacy, University of Florida, 1333 Center Drive, Gainesville, FL, 32610, United States. Electronic address: [email protected].
PMID: 40239483 DOI: 10.1016/j.ejmech.2025.117624
Abstract

BCL-XL is a crucial anti-apoptotic protein involved in tumorigenesis and resistance to Cancer chemotherapy. Transitioning from conventional inhibitors to PROTAC degraders has shown promising potential, particularly in minimizing the on-target thrombocytopenia linked to BCL-XL inhibition. However, reported BCL-XL degraders were mostly derived from BCL-XL/Bcl-2 dual inhibitor ABT-263, which also inhibits or degrades Bcl-2 and can potentially cause neutropenia when combined with conventional chemotherapy as seen with ABT-263 in the clinic. The goal of the present study is to develop a highly specific BCL-XL degrader without Bcl-2 inhibition/degradation. In this study, XZ338, a highly potent and selective BCL-XL degrader derived from BCL-XL specific inhibitor A-1331852, was generated. XZ338 is 70-fold more potent than ABT-263 against MOLT-4 T-ALL cells, with over 89-fold selectivity for MOLT-4 cells over human platelets.

Keywords
Apoptosis; BCL-2; BCL-X(L); PROTAC; Platelet.
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