Thalidomide derivatives degrade BCL-2 by reprogramming the binding surface of CRBN
Why this work is in the frame
A frame that forgets how it found something cannot be audited. These are the routes that admitted this work.
Bibliographic record
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.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it