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
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Can alkenyl oxindoles recruit a new E3 ligase for PROTACs?
These passages occur verbatim in the stored paper text. They support the points listed below; they do not verify every statement in the explanation.
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
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.
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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.