chemical-biology
Can alkenyl oxindoles recruit a new E3 ligase for PROTACs?
Open access · cc by · source: Europe PMC
Alkenyl oxindole PROTAC ligands recruit CRL4-DCAF11 to degrade targets like BRD4; lead HL435 reached >99% Dmax with nanomolar DC50 in breast cancer cells.
Key findings
Alkenyl oxindoles act as novel E3 ligands recruiting CRL4-DCAF11. HL435 achieved Dmax >99% with DC50 11.9 nM (MDA-MB-231) and 21.9 nM (MCF-7), with BRD4 loss within ~1 hour.
Methodology
Conjugated alkenyl oxindoles to BRD4 inhibitor JQ1, ran SAR to find degraders, showed UPS-dependent BRD4 loss via CRL4-DCAF11, and tested potent molecule HL435 in cells and a mouse xenograft.
Limitations
Not a clinical trial; human safety, bioavailability, and off-target degradation profiles remain to be established beyond preclinical models.
How this study connects
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