Entinostat-based PROTACs preferentially degrade HDAC3 in colorectal cancer models
- Two PROTAC series were built on the HDAC inhibitor entinostat, recruiting either VHL or CRBN E3 ligases.
- A representative from each series drove time-dependent HDAC loss, favouring HDAC3, followed by apoptosis and lower viability in colorectal cancer models.
- Activity was tested in patient-derived organoids and a CAM model, with p21 and the stemness markers CD44 and LGR5 probing acetylation-driven gene regulation.
💡 Points Based on the abstract
Preferential HDAC3 loss may partly reflect the entinostat warhead's own isoform profile, so the first things to look for are a non-binding or inactive-epimer control and a way to separate degradation from inhibition, such as HDAC3 knockout or proteasome and neddylation blockade. A comparison with other HDAC3-selective PROTACs would also show whether the VHL versus CRBN choice shapes isoform bias.
HDAC3 degradation to uncover therapeutic vulnerability in colorectal cancer ↗