Development of potent and selective tetrahydro-β-carboline-based HDAC6 inhibitors with promising activity against triple-negative breast cancer.

ABSTRACT: Overexpression of histone deacetylase 6 (HDAC6) is implicated in tumorigenesis, invasion, migration, survival, apoptosis, and growth of various malignancies, making it a promising target for cancer treatment. Building on our previous work, we report a novel series of tetrahydro-β-carboline-piperazinedione derivatives as HDAC6 inhibitors. Structural modifications were introduced at the 6-aryl group, with the m-bromophenyl derivative (9c) emerging as the most potent HDAC6 inhibitor, exhibiting an IC₅₀ of 7 nM. Compound 9c demonstrated robust growth inhibitory activity across 60 cancer cell lines from the NCI panel, with a mean GI₅₀ of 2.64 μM and a GI₅₀ below 5 μM for nearly all tested lines, while exhibiting significantly lower cytotoxicity towards no

SUBMITTER: Fathy A 

PROVIDER: S-EPMC12004265 | biostudies-literature | 2025 Apr

REPOSITORIES: biostudies-literature