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AlphaFold modeling, BCL-2 degradation, chemically induced proximity, CRBN ligase, Drosophila tumor model, molecular glue degrader, oncogenomics, targeted protein degradation, thalidomide derivatives, venetoclax resistance
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.
