# Targeted HDAC8 inhibition with non-hydroxamate [1,2,4]triazolo[4,3-a] quinoline compounds

## TL;DR

Researchers developed new HDAC8 inhibitors that effectively target neuroblastoma cells without harming normal cells.

## Contribution

A novel series of non-hydroxamate [1,2,4]triazolo[4,3-a]quinoline compounds were designed as potent HDAC8 inhibitors.

## Key findings

- Compounds 9h and 9m showed strong efficacy in IMR-32 neuroblastoma cells but minimal effects on other cancer and normal cells.
- Molecular docking and dynamics simulations confirmed stable interactions within the HDAC8 active site.
- Increased SMC3 acetylation levels suggest effective HDAC8 inhibition without altering total SMC3 protein.

## Abstract

Histone deacetylase 8 (HDAC8) is a key enzyme involved in regulating gene expression and tumor development, positioning it as an attractive target for neuroblastoma. In this work, we designed and synthesized a novel series of substituted [1,2,4]Triazolo[4,3-a]quinoline derivatives to investigate their potential as HDAC8 inhibitors. Structural insights into their inhibitory activity were gained through molecular docking studies, highlighting critical interactions within the HDAC8 active site. To assess the stability of these interactions, molecular dynamics simulations were performed, confirming that the compounds maintained strong and stable binding within the HDAC8 enzyme. The most promising inhibitors 9h and 9m demonstrated significant efficacy in IMR-32 neuroblastoma cells, but had much weaker effects on the HCT116 and MCF7 cancer cell lines, as well as on the normal control cell line, HEK293. Further biological evaluations, including colony formation and cell migration assays, revealed their potential to inhibit the growth and spread of neuroblastoma tumor cells. Additional studies on cell cycle progression, apoptosis induction, and SMC3 acetylation indicated increased acetylation levels without altering total SMC3 protein levels, suggesting effective HDAC8 target engagement. In summary, comprehensive molecular modelling and biological assessments have demonstrated the strong potential of these non-hydroxamate-based HDAC8 inhibitors for treating neuroblastoma.

The online version contains supplementary material available at 10.1038/s41598-026-38490-y.