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.
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Can alkenyl oxindoles recruit a new E3 ligase for PROTACs?
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HL435 Dmax >99%; DC50 11.9 nM (MDA-MB-231) and 21.9 nM (MCF-7).
The maximum degradation efficiency (D max ) of HL435 was >99%, with DC 50 values of 11.9 and 21.9 nM in MDA-MB-231 and MCF-7 cells, respectively ( Fig 2C ).
BRD4 degradation observed by 1 hour after HL435.
Kinetics study of BRD4 degradation showed that degradation was observed just 1 hour after HL435 treatment (Figs 2D and S3B ), with a half-life of 1.38 and 1.31 hour in MDA-MB-231 and MCF-7 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.
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