Bivalent ligands as a new universal chemotype of BCL6 degrader by inducing aggregation
Hu, R.; Hu, X.-T.; Yang, Y.-Y.; Luo, P.; Li, C.-H.; Liu, Z.-H.; Yu, L.-T.; Wang, N.-Y.
Show abstract
BCL6 naturally exists as a homodimer to exert its transcriptional repressive function. Previous studies shown that molecular glue BI3802 can induce BCL6 dimer polymerization and thus degradation by ubiquitin-proteasome system. In this study we proposed a new strategy to degrade BCL6 by its homo-bivalent ligands, which can be rationally designed by assemble two BCL6 BTB ligands via linker. These homo-bivalent degraders (HBiDs) can induce polymerization of BCL6 dimer through chain assembly and ultimately lead to its ubiquitination and degradation. Since HBiD does not require a fragment to interact with components of protein degradation system, it could exhibit better target selectivity than traditional protein degraders while avoid drug resistance caused by mutations in protein degradation components. Here we will provide the proof-of-concept evidences for HBiD as BCL6 degrader. Most HBiDs synthesized in this study could degrade BCL6 regardless of the chemotype of BCL6 ligands, with extraordinary target selectivity. The degradation of BCL6 depends on the aggregation of BCL6 dimer induced by HBiD and the recruitment of SIAH1, the natural E3 ligase of BCL6. As protein dimerization is a common phenomenon in cells, HBiD may provide us with a powerful strategy for designing protein degraders as drug candidates or molecular probes.
Matching journals
The top 12 journals account for 50% of the predicted probability mass.
Similar papers in this journal
Similar papers in this journal
- Temporal and Spatial Characterization of CUL3KLHL20-driven Targeted Degradation of BET family, BRD Proteins by the Macrocycle-based Degrader BTR2004 94%
- Rational development of a small-molecule activator of CK1γ2 that decreases C99 and beta-amyloid levels 92%
- A High-throughput Fluorescence Polarization Assay for Screening Sirtuin Inhibitors 92%
Similar papers in this journal
- Construction of High Content Nanobody Library in Mammalian Cells by Linear-double-stranded DNA Based Strategies 91%
- Efficient chemical and enzymatic syntheses of FAD nucleobase analogues and their analysis as enzyme cofactors 91%
- Site-specific phosphorylation of Huntingtin exon 1 recombinant proteins enabled by the discovery of novel kinases 90%
Similar papers in this journal
Similar papers in this journal
- Water-soluble 4-(dimethylaminomethyl)heliomycin exerts greater antitumor effects than parental heliomycin by targeting the tNOX-SIRT1 axis and apoptosis in oral cancer cells 94%
- Discovery and biological evaluation of a potent small molecule CRM1 inhibitor for its selective ablation of extranodal NK/T cell lymphoma 94%
- A survey of optimal strategy for signature-based drug repositioning and an application to liver cancer 93%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.