2. Academic Validation
  3. Unlocking the potential of novel tetrahydro-β-carboline-based HDAC6 inhibitors for colorectal cancer therapy: Design, synthesis and biological evaluation

Unlocking the potential of novel tetrahydro-β-carboline-based HDAC6 inhibitors for colorectal cancer therapy: Design, synthesis and biological evaluation

  • Bioorg Chem. 2025 Jun 15:160:108454. doi: 10.1016/j.bioorg.2025.108454.
Noreen Hemida 1,  Dalia S El-Gamil 2,  Ahmed K ElHady 3,  Kai-Chun Lin 4,  Yen-Hua Chang 4,  Sebastian Hilscher 5,  Mike Schutkowski 5,  Hany S Ibrahim 5,  Mostafa M Hamed 6,  Shun-Hua Chen 7,  Chun-Hong Chen 8,  Ashraf H Abadi 1,  Wolfgang Sippl 5,  Po-Jen Chen 9,  Yi-Sheng Cheng 10,  Mohammad Abdel-Halim 11
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt.
  • 2 Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt; Department of Chemistry, Faculty of Pharmacy, Ahram Canadian University, Cairo 12451, Egypt.
  • 3 Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt; School of Life & Medical Sciences, University of Hertfordshire hosted by Global Academic Foundation, New Administrative Capital, Cairo, Egypt.
  • 4 Institute of Plant Biology, College of Life Science, National Taiwan University, Taipei 10617, Taiwan.
  • 5 Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, Halle (Saale), Germany.
  • 6 Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research, Saarland University Campus, 66123 Saarbrücken, Germany.
  • 7 School of Nursing, Fooyin University, Kaohsiung 831301, Taiwan.
  • 8 Department of Medical Research, E-Da Hospital and Graduate Institute of Medicine, I-Shou University, Kaohsiung 824410, Taiwan.
  • 9 Department of Medical Research, E-Da Hospital and Graduate Institute of Medicine, I-Shou University, Kaohsiung 824410, Taiwan; Department of Pharmacology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan. Electronic address: ed113510@edah.org.tw.
  • 10 Institute of Plant Biology, College of Life Science, National Taiwan University, Taipei 10617, Taiwan; Department of Life Science, College of Life Science, National Taiwan University, Taipei 10617, Taiwan; Genome and Systems Biology Degree Program, College of Life Science, National Taiwan University, Taipei 10617, Taiwan.
  • 11 Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt. Electronic address: mohammad.abdel-halim@guc.edu.eg.
PMID: 40252366 DOI: 10.1016/j.bioorg.2025.108454
Abstract

Altered 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.

Keywords

Anti-cancer agents; Anti-tumor immunity; Colon cancer; Histone deacetylase (HDAC) 6; Tetrahydro-β-carboline.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-172791
    HDAC6 Inhibitor