2. Academic Validation
  3. Discovery of XZ338, a highly potent BCL-XL degrader

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

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: zhoud@uthscsa.edu.
  • 6 Department of Medicinal Chemistry and College of Pharmacy, University of Florida, 1333 Center Drive, Gainesville, FL, 32610, United States. Electronic address: zhengg@cop.ufl.edu.
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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