Noreen HemidaDalia S. El-GamilAhmed K. ElHadyKai-Chun LinYen-Hua ChangSebastian HilscherMike SchutkowskiHany S. IbrahimMostafa M. HamedShun-Hua ChenChun-Hong ChenAshraf H. AbadiWolfgang SipplPo-Jen ChenYI-SHENG CHENGMohammad Abdel-Halim2025-05-262025-05-262025-06-15https://www.scopus.com/record/display.uri?eid=2-s2.0-105002852699&origin=resultslisthttps://scholars.lib.ntu.edu.tw/handle/123456789/729697Altered histone deacetylase 6 (HDAC6) expression and function have been linked to cancer progression, positioning it as a promising therapeutic target for cancer treatment. Herein, we introduce HDAC6 inhibitors based on the tetrahydro-β-carboline scaffold, with compound 18d exhibiting the strongest HDAC6 inhibitory potency, achieving an IC50 of 1.3 nM. Compound 18d exhibited significant growth inhibitory activity against an NCI panel of 60 human cancer cell lines with a minimal cytotoxic effect on non-tumor cells. In vitro mechanistic investigations were conducted in HCT-116 colorectal cancer cells where the capability of 18d to enhance the acetylation of α-tubulin (HDAC6 substrate) rather than nuclear H3 histone (HDAC1 substrate) confirmed selective inhibition of HDAC6 subtype. Additionally, compound 18d was observed to suppress the S phase and promote accumulation in the apoptotic sub-G1 phase, potentially through increasing cleaved caspase 3 and reducing Bcl-2 levels in HCT-116 cells. A wound healing assay also elicited the ability of 18d to hinder cell migration. Notably, 18d could suppress the phosphorylation of extracellular signal-regulated kinase (ERK)1/2, a crucial signaling pathway implicated in cancer cell proliferation, migration and apoptosis. Moreover, downregulation of the critical immune checkpoint protein programmed death-ligand 1 (PD-L1) revealed a potential role of 18d in augmenting immune response towards tumor cells. In summary, these findings highlight 18d's dual role in direct tumor growth suppression and immune system sensitization, highlighting a broader cancer therapeutic potential beyond conventional HDAC inhibition.enAnti-cancer agentsAnti-tumor immunityColon cancerHistone deacetylase (HDAC) 6Tetrahydro-β-carboline[SDGs]SDG3journal article10.1016/j.bioorg.2025.108454