Targeting Class I Histone Deacetylases Triggers Antitumor Responses in Colorectal Cancer In Vitro and In Vivo

Area of Science:

• Medicinal Chemistry
• Cancer Biology
• Molecular Pharmacology

Background:

• Class I histone deacetylases (HDACs) are overexpressed in colorectal cancer (CRC), contributing to tumor progression.
• Targeting HDACs is a validated strategy for cancer therapy, but selectivity remains a challenge.

Purpose of the Study:

• To develop novel, selective class I HDAC inhibitors (HDACis) for colorectal cancer treatment.
• To evaluate the antiproliferative effects and mechanisms of action of lead compounds in CRC models.

Main Methods:

• Computational, synthetic, and biological approaches were used to design and optimize *o*-aminobenzamide-based HDACis.
• In vitro assays assessed antiproliferative activity, cytotoxicity, HDAC inhibition, cell cycle effects, apoptosis, and autophagy.
• In vivo efficacy was evaluated using the chick chorioallantoic membrane (CAM) assay.

Main Results:

• Compounds 5d (Colrestat) and 5i demonstrated potent antiproliferative effects against CRC cells with minimal toxicity to healthy colon cells.
• Both compounds induced G2/M cell cycle arrest; 5d showed high selectivity for class I HDACs (IC50s: 41.2 nM for HDAC1, 52.5 nM for HDAC2, 74.3 nM for HDAC3).
• 5d induced H3K9 acetylation and p21 upregulation, while 5i triggered apoptosis; both compounds exhibited significant in vivo antitumor efficacy, outperforming entinostat.

Conclusions:

• Novel *o*-aminobenzamide-based HDACis, particularly 5d (Colrestat), are highly selective inhibitors of class I HDACs.
• These compounds exhibit potent anti-CRC activity through distinct mechanisms, including cell cycle arrest and apoptosis induction.
• The developed HDACis show promising therapeutic potential for colorectal cancer treatment.