Can alkenyl oxindoles recruit a new E3 ligase for PROTACs?
Alkenyl oxindole PROTAC ligands recruit CRL4-DCAF11 to degrade targets like BRD4; lead HL435 reached >99% Dmax with nanomolar DC50 in breast cancer cells.
Source
Alkenyl oxindole is a novel PROTAC moiety that recruits the CRL4DCAF11 E3 ubiquitin ligase complex for targeted protein degradation
What they did
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.
What they found
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.
The limits
What it doesn't show
Not a clinical trial; human safety, bioavailability, and off-target degradation profiles remain to be established beyond preclinical models.
Key terms
- PROTAC
- Heterobifunctional degrader linking a target ligand to an E3-recruiting ligand.
- E3 ubiquitin ligase
- Enzyme complex that tags proteins with ubiquitin for proteasomal destruction.
- DCAF11 / CRL4
- Cullin-RING ligase substrate receptor engaged by alkenyl oxindoles here.
- BRD4
- Bromodomain protein targeted via JQ1 conjugates in this study.
- DC50
- Concentration achieving 50% maximal target degradation.
- Alkenyl oxindole
- Chemical moiety proposed as a novel E3-recruiting PROTAC handle.
Flashcards
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E3 complex recruited by alkenyl oxindoles:
Common questions
Which E3 complex is recruited?
CRL4-DCAF11.
Lead compound?
HL435.
DC50 in MDA-MB-231?
11.9 nM (Dmax >99%).
Why it matters?
Expands the small set of E3 ligases usable for PROTACs.