Non-peptide macrocyclic histone deacetylase inhibitors

Area of Science:

• Medicinal Chemistry
• Cancer Therapeutics
• Molecular Biology

Background:

• Histone deacetylase inhibitors (HDACi) are a promising cancer therapy, but macrocyclic depsipeptides have complex structures limiting structure-activity relationship (SAR) studies.
• Existing macrocyclic HDACi often retain a peptidyl backbone, restricting modifications and biological activity modulation.

Purpose of the Study:

• To discover a new class of macrocyclic HDACi with a non-peptide backbone for improved SAR studies and therapeutic potential.
• To investigate the HDAC inhibition activities and isoform selectivity of these novel compounds.

Main Methods:

• Discovery of novel macrocyclic HDACi based on macrolide antibiotic skeletons.
• Structure-activity relationship (SAR) studies to evaluate HDAC inhibition.
• Assessment of selectivity against different HDAC isoforms (e.g., HDAC 1, 2, and 8).

Main Results:

• Identified a new class of non-peptide macrocyclic HDACi with low nanomolar IC(50) values.
• Demonstrated linker-length and macrolide-type dependent HDAC inhibition.
• Observed subclass selectivity, with compounds being more selective against HDACs 1 and 2 compared to HDAC 8.

Conclusions:

• The novel macrolide-based macrocyclic HDACi offer a promising alternative to peptide-based inhibitors for cancer therapy.
• These compounds facilitate improved SAR studies and exhibit desirable subclass HDAC isoform selectivity.