Development of potent and selective tetrahydro-β-carboline-based HDAC6 inhibitors with promising activity against triple-negative breast cancer
Journal
RSC Medicinal Chemistry
ISSN
2632-8682
Date Issued
2025-04-17
Author(s)
Aya Fathy
Amro Allam
Ahmed K. ElHady
Dalia S. El-Gamil
Kai-Chun Lin
Yen-Hua Chang
Yu-Hsuan Lee
Sebastian Hilscher
Mike Schutkowski
Hany S. Ibrahim
Shun-Hua Chen
Chun-Hong Chen
Ashraf H. Abadi
Wolfgang Sippl
Po-Jen Chen
Mohammad Abdel-Halim
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 non-tumor cell lines. The triple-negative breast cancer cell line MDA-MB-231 was selected for further investigation of 9c's cellular effects. 9c selectively increased the acetylation of non-histone α-tubulin in MDA-MB-231 cells, confirming its HDAC6 selectivity.
Furthermore, 9c effectively induced apoptosis, caused apoptotic sub-G1 phase accumulation, upregulated pro-apoptotic caspase-3, and downregulated anti-apoptotic Bcl-2. Notably, 9c reduced the expression of programmed death-ligand 1 (PD-L1), a key immune checkpoint protein that enables tumor cells to evade immune surveillance, highlighting its potential role in enhancing anti-tumor immunity. In addition, 9c inhibited phosphorylated extracellular signal-regulated kinase (ERK)1/2, a central signaling pathway that drives cell proliferation, survival, and migration, further highlighting its significance in suppressing tumor progression and growth. In migration assays, 9c impaired cell motility, achieving 80 percent gap closure inhibition in a wound-healing assay. Collectively, these findings underline compound 9c as a highly promising candidate for the treatment of triple-negative breast cancer, with the added benefits of PD-L1 and ERK inhibition for potential synergy in enhancing anti-tumor immunity and reducing tumor cell proliferation.
Publisher
Royal Society of Chemistry (RSC)
Type
journal article