Comprehensive Transcriptomic Analysis of Novel Class I HDAC Proteolysis Targeting Chimeras (PROTACs)

Area of Science:

• Epigenetics and Molecular Oncology
• Drug Discovery and Development

Background:

• Class I histone deacetylases (HDAC1-3) are key regulators of gene expression and chromatin structure.
• HDAC inhibition shows therapeutic promise in hematological cancers.
• Previous PROTACs targeting HDACs utilized the VHL E3 ligase.

Purpose of the Study:

• To develop novel PROTACs targeting HDAC1-3 using cellular inhibitor of apoptosis (IAP) E3 ligases.
• To compare the efficacy of IAP-based PROTACs against VHL-based PROTACs in cancer cells.

Main Methods:

• Synthesis and characterization of novel IAP-based PROTACs (JPS026, JPS027).
• Assessment of HDAC1-3 degradation and histone acetylation induction.
• Evaluation of cell death in HCT116 cells.
• RNA sequencing analysis to determine gene expression changes.

Main Results:

• Both VHL- and IAP-based PROTACs effectively degrade HDAC1-3 and increase histone acetylation.
• The IAP-based PROTAC JPS026 demonstrated significantly higher potency in inducing cell death in HCT116 cells compared to the VHL-based PROTAC JPS004.
• PROTAC treatment led to repression of cell cycle and DNA replication genes, reduced mTORC1/2 components, and increased FOXO3-regulated autophagy and apoptosis genes.

Conclusions:

• Novel PROTACs combining HDAC and IAP ligands are potent inducers of apoptosis and differential gene expression.
• IAP-based PROTACs offer a promising strategy for cancer therapy by targeting HDACs.
• These findings highlight a new approach for developing targeted cancer therapeutics.