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Journal Article

Thalidomide derivatives degrade BCL-2 by reprogramming the binding surface of CRBN

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Heinz,  Marcel       
Department of Theoretical Biophysics, Max Planck Institute of Biophysics, Max Planck Society;

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Hummer,  Gerhard       
Department of Theoretical Biophysics, Max Planck Institute of Biophysics, Max Planck Society;
Institute of Biophysics, Goethe University, Frankfurt am Main, Germany;

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Citation

Wang, J., Heinz, M., Han, K., Shah, V. J., Hasselbeck, S., Schwalm, M. P., et al. (2024). Thalidomide derivatives degrade BCL-2 by reprogramming the binding surface of CRBN. Cell Reports Physical Science, 5(5): 101960. doi:10.1016/j.xcrp.2024.101960.


Cite as: https://hdl.handle.net/21.11116/0000-000F-76A5-2
Abstract
Recent studies demonstrate that modified thalidomide chemically alters the binding surface of its binding E3 ligase, CRBN, leading to the degradation of new substrate proteins. In this study, we conduct a proteome-wide analysis of thalidomide-like compounds and pinpoint three derivatives (C5, C6, and C7) that specifically target and degrade the BCL-2 protein. Using AlphaFold-driven molecular modeling combined with experimental data, we suggest that GLY128, ALA131, and THR132 are crucial in forming a CRBN-C5-BCL-2 ternary complex. This interaction is notably distinct from that of venetoclax, a known clinical BCL-2 inhibitor that interacts with the BH3 domain. Significantly, these thalidomide derivatives have the ability to degrade BCL-2 mutations that are resistant to venetoclax, thereby enhancing survival rates in a Notch-depleted Drosophila intestinal tumor model. Our findings highlight the critical role of targeted modifications to the E3 ligase surface in altering its binding affinity and achieving a new substrate protein profile.