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

Wang, Jianhui; Heinz, Marcel; Han, Kang; Shah, Varun J.; Hasselbeck, Sebastian; Schwalm, Martin P.; Rathore, Rajeshwari; Hummer, Gerhard; Zhou, Jun; Dikic, Ivan; Cheng, Xinlai

doi:10.1016/j.xcrp.2024.101960

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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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引用

Wang, J., Heinz, M., Han, K., Shah, V. J., Hasselbeck, S., Schwalm, M. P., Rathore, R., Hummer, G., Zhou, J., Dikic, I., & Cheng, X. (2024). Thalidomide derivatives degrade BCL-2 by reprogramming the binding surface of CRBN. Cell Reports Physical Science, 5(5). doi:10.1016/j.xcrp.2024.101960.

引用: https://hdl.handle.net/21.11116/0000-000F-76A5-2

要旨

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.