HDAC3 degradation to uncover therapeutic vulnerability in colorectal cancer

Overcoming therapeutic resistance in colorectal cancer (CRC) remains a major clinical challenge, highlighting the need for strategies targeting epigenetic drivers. Targeted protein degradation emerged as a powerful approach to selectively eliminate disease-relevant proteins. We reported the development of two series of PROTACs based on the clinical-stage HDAC inhibitor entinostat, by recruiting either VHL or CRBN E3 ligases. Compounds 4b and 4h, representative of the two series of degraders, induced robust, time-dependent HDAC degradation with a clear-cut preference for HDAC3, leading to apoptosis and reduced viability in CRC models. The antitumor activity of the new degraders was proved in patient-derived colon cancer organoids and in the CRC CAM model. The role of acetylation in gene regulation and expression in CRC was investigated measuring p21 and stemness markers such as CD44 and LGR5. Collectively, these findings demonstrate that new degraders effectively target HDAC3 and exert anti-tumor activity across multiple CRC models.