Discovery of XZ338, a highly potent BCL-XL degrader
BCL-X<sub>L</sub> 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-X<sub>L</sub> inhibition. However, reported BCL-X<sub>L</sub> degraders were mostly derived from BCL-X<sub>L</sub>/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-X<sub>L</sub> degrader without BCL-2 inhibition/degradation. In this study, XZ338, a highly potent and selective BCL-X<sub>L</sub> degrader derived from BCL-X<sub>L</sub> 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.
Authors
- Wanyi Hu
- Xingui Liu (ORCID: https://orcid.org/0000-0003-2659-8007)
- Dinesh Thummuri (ORCID: https://orcid.org/0000-0002-6027-0999)
- Guangrong Zheng (ORCID: https://orcid.org/0000-0002-8106-6663)
- Xuan Zhang (ORCID: https://orcid.org/0000-0001-6062-6708)
- Daohong Zhou (ORCID: https://orcid.org/0000-0002-2400-6461)
- Shuo Zhou (ORCID: https://orcid.org/0000-0001-8684-8341)
- Peiyi Zhang (ORCID: https://orcid.org/0000-0003-0207-1112)
Institutions
- The University of Texas at San Antonio Health Science Center (US)
- American Association of Colleges of Pharmacy (US)
- University of Florida (US)
- Florida College (US)
Publication Details
- Journal
- European Journal of Medicinal Chemistry
- Published
- 2025-04-15
- DOI
- https://doi.org/10.1016/j.ejmech.2025.117624
- Citations
- 4
- Primary Topic
- Semiconductor materials and devices
- Type
- article
- Field-Weighted Citation Impact
- 2.92
Funders
- National Institutes of Health
- National Cancer Institute