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

• Published in: RSC medicinal chemistry Vol. 16; no. 6; pp. 2754 - 2784
• Main Authors: Fathy, Aya, Allam, Amro, ElHady, Ahmed K, El-Gamil, Dalia S, Lin, Kai-Chun, Chang, Yen-Hua, Lee, Yu-Hsuan, Hilscher, Sebastian, Schutkowski, Mike, Ibrahim, Hany S, Chen, Shun-Hua, Chen, Chun-Hong, Abadi, Ashraf H, Sippl, Wolfgang, Chen, Po-Jen, Cheng, Yi-Sheng, Abdel-Halim, Mohammad
• Format: Journal Article
• Language: English
• Published: England RSC 17.04.2025
• Subjects: Chemistry
• ISSN: 2632-8682; 2632-8682
• DOI: 10.1039/d5md00086f

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 IC 50 of 7 nM. Compound 9c demonstrated robust growth inhibitory activity across 60 cancer cell lines from the NCI panel, with a mean GI 50 of 2.64 μM and a GI 50 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% 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. 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.