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Discovery of XZ338, a highly potent BCL-XL degrader
Xuan Zhang1, Dinesh Thummuri2, Wanyi Hu1
1Department of Medicinal Chemistry and College of Pharmacy, University of Florida, 1333 Center Drive, Gainesville, FL, 32610, United States.
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.
Insights
A new BCL-XL degrader, XZ338, offers potent and selective cancer cell targeting. This PROTAC degrader minimizes on-target side effects like thrombocytopenia, unlike previous dual inhibitors.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- BCL-XL is a key anti-apoptotic protein implicated in cancer development and chemotherapy resistance.
- Current BCL-XL inhibitors can cause on-target thrombocytopenia.
- Existing BCL-XL degraders may also inhibit BCL-2, leading to potential neutropenia with chemotherapy.
Purpose of the Study:
- To develop a novel, highly specific BCL-XL degrader.
- To create a degrader that avoids BCL-2 inhibition or degradation.
- To overcome the limitations of existing BCL-XL-targeting agents.
Main Methods:
- Generation of a PROTAC degrader (XZ338) derived from a selective BCL-XL inhibitor (A-1331852).
- Evaluation of potency and selectivity against cancer cells and platelets.
- Comparative analysis with existing dual inhibitors like ABT-263.
Main Results:
- XZ338 demonstrated high potency against MOLT-4 T-ALL cells, being 70-fold more effective than ABT-263.
- XZ338 exhibited over 89-fold selectivity for MOLT-4 cells compared to human platelets.
- The developed degrader is specific for BCL-XL without affecting BCL-2.
Conclusions:
- XZ338 represents a highly potent and selective BCL-XL degrader.
- This agent offers a promising therapeutic strategy with reduced risk of thrombocytopenia.
- XZ338 provides a safer alternative for targeting BCL-XL in cancer therapy.
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