Development of new pyrazoles as class I HDAC inhibitors: Synthesis, molecular modeling, and biological characterization in leukemia cells.
Francesco BerlutiFady BaseliousSven HagemannSebastian HilscherMatthias SchmidtStefan HüttelmaierMike SchutkowskiWolfgang SipplHany S IbrahimPublished in: Archiv der Pharmazie (2024)
Class I histone deacetylases (HDACs) are considered promising targets in current cancer research. To obtain subtype-selective and potent HDAC inhibitors, we used the aminobenzamide scaffold as the zinc-binding group and prepared new derivatives with a pyrazole ring as the linking group. The synthesized compounds were analyzed in vitro using an enzymatic assay against HDAC1, -2, and -3. Compounds 12b, 15b, and 15i were found to be potent HDAC1 inhibitors, also in comparison to the reference compounds entinostat and tacedinaline, with IC 50 values of 0.93, 0.22, and 0.68 μM, respectively. The best compounds were measured for their cellular effect and target engagement in acute myeloid leukemia (AML) cells. In addition, we studied the interaction of the compounds with HDAC subtypes using docking and molecular dynamic simulations. In summary, we have developed a new chemotype of HDAC1 inhibitors that can be used for further structure-based optimization.
Keyphrases
- histone deacetylase
- induced apoptosis
- acute myeloid leukemia
- cell cycle arrest
- molecular dynamics
- cell death
- dna methylation
- bone marrow
- endoplasmic reticulum stress
- gene expression
- high throughput
- transcription factor
- squamous cell carcinoma
- social media
- acute lymphoblastic leukemia
- nitric oxide
- molecular docking
- cell proliferation
- binding protein
- protein protein
- allogeneic hematopoietic stem cell transplantation
- lymph node metastasis