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Discovery of a Novel BCL-XL PROTAC Degrader with Enhanced BCL-2 Inhibition
Pratik Pal1, Dinesh Thummuri2, Dongwen Lv2
1Department of Medicinal Chemistry, College of Pharmacy, University of Florida, 1333 Center Drive, Gainesville, Florida 32610, United States.
Abstract:
BCL-XL and BCL-2 are important targets for cancer treatment. BCL-XL specific proteolysis-targeting chimeras (PROTACs) have been developed to circumvent the on-target platelet toxicity associated with BCL-XL inhibition. However, they have minimal effects on cancer cells that are dependent on BCL-2 or both BCL-XL and BCL-2. Here we report a new series of BCL-PROTACs. The lead PZ703b exhibits high potency in inducing BCL-XL degradation and in inhibiting but not degrading BCL-2, showing a hybrid dual-targeting mechanism of action that is unprecedented in a PROTAC molecule. As a result, PZ703b is highly potent in killing BCL-XL dependent, BCL-2 dependent, and BCL-XL/BCL-2 dual-dependent cells in an E3 ligase (VHL)-dependent fashion. We further found that PZ703b forms stable {BCL-2:PROTAC:VCB} ternary complexes in live cells that likely contribute to the enhanced BCL-2 inhibition by PZ703b. With further optimization, analogues of PZ703b could potentially be developed as effective antitumor agents by co-targeting BCL-XL and BCL-2.
Insights
New proteolysis-targeting chimeras (PROTACs) degrade BCL-XL and inhibit BCL-2, effectively killing cancer cells dependent on either or both proteins. This dual-targeting approach offers a novel strategy for cancer therapy.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- BCL-XL and BCL-2 are crucial regulators of cell survival and key targets in cancer therapy.
- BCL-XL-specific PROTACs aim to reduce platelet toxicity but are ineffective against BCL-2-dependent cancers.
- A need exists for novel agents targeting both BCL-XL and BCL-2.
Purpose of the Study:
- To develop and characterize novel PROTACs with a dual-targeting mechanism against BCL-XL and BCL-2.
- To evaluate the efficacy of these PROTACs in various cancer cell models.
- To elucidate the mechanism of action of the lead compound.
Main Methods:
- Synthesis and characterization of a new series of BCL-PROTACs.
- Assessment of protein degradation and inhibition in cancer cells.
- Evaluation of cell killing in BCL-XL-dependent, BCL-2-dependent, and dual-dependent cell lines.
- Analysis of ternary complex formation in live cells.
Main Results:
- The lead compound, PZ703b, potently induces BCL-XL degradation and inhibits BCL-2 without degrading it.
- PZ703b demonstrates potent anti-cancer activity across BCL-XL-dependent, BCL-2-dependent, and dual-dependent cancer cells.
- Formation of stable {BCL-2:PROTAC:VCB} ternary complexes was observed, contributing to enhanced BCL-2 inhibition.
- The observed activity is dependent on the E3 ligase VHL.
Conclusions:
- PZ703b exhibits an unprecedented hybrid dual-targeting mechanism of action for a PROTAC.
- This novel class of PROTACs shows significant potential as antitumor agents.
- Further optimization could lead to effective therapies co-targeting BCL-XL and BCL-2 for diverse cancers.
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