Rational design of potent small molecule SMARCA2/A4 (BRM/BRG1) degraders acting via the recruitment of FBXO22
Villemure, E.; Yauch, R. L.; Rudolph, J.; Januario, T.; Zeng, M.; Budayeva, H. G.; Walters, B. T.; Lictao, A.; Li, S. K.; Ye, X.; Gilchrist, C. L.; Hoag, B.; Endres, N. F.; Hsu, P. L.; Chan, J.; Cheung, T. K.; Costa, M. R.; Fortin, J.-P.; Ishisoko, N.; Babin, B. M.; Liu, J.
Show abstract
Target-anchored monovalent degraders are more drug-like than their bivalent counterparts, Proteolysis Targeting Chimeras (PROTACs), while offering greater target specificity control than the E3 ligase-anchored monovalent degraders, also known as molecular glues. However, their discovery has typically been serendipitous, and the rules governing their identification remain unclear. This study focused on the intentional discovery of SMARCA2/A4 monovalent degraders using a library based on SMARCA2/A4 bromodomain-binding ligands. Compound G-6599 emerged as a lead candidate, showing exceptional degradation potency and specificity for SMARCA2/A4. Mechanistic studies revealed that G-6599 operates through the ubiquitin-proteasome pathway and the E3 ligase FBXO22. G-6599 was shown to promote ternary complex formation between SMARCA2 and FBXO22 involving covalent conjugation to a cysteine residue on the latter. Unlike other recently identified FBXO22-dependent degraders, it does not require biotransformation. The selective degradation ability of G-6599, along with its unique mechanism, highlights the therapeutic potential of target-anchored monovalent degraders.
Matching journals
The top 3 journals account for 50% of the predicted probability mass.
Similar papers in this journal
Similar papers in this journal
- Peptide-mediated inhibition of the transcriptional regulator Elongin BC induces apoptosis in cancer cells 97%
- A direct high-throughput protein quantification strategy facilitates discovery and characterization of a celastrol-derived BRD4 degrader 96%
- Chemoproteomics-Enabled Discovery of a Covalent Molecular Glue Degrader Targeting NF-κB 95%
Similar papers in this journal
- SDR enzymes oxidize specific lipidic alkynylcarbinols into cytotoxic protein-reactive species 97%
- Branched ubiquitin chain binding and deubiquitination by UCH37 facilitate proteasome clearance of stress-induced inclusions 96%
- Selective inhibition reveals the regulatory function of DYRK2 in protein synthesis and calcium entry 96%
"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.