PUBLICATION
Discovery of 1-Benzhydryl-Piperazine-Based HDAC Inhibitors with Anti-Breast Cancer Activity: Synthesis, Molecular Modeling, In Vitro and In Vivo Biological Evaluation
- Authors
- Ruzic, D., Ellinger, B., Djokovic, N., Santibanez, J.F., Gul, S., Beljkas, M., Djuric, A., Ganesan, A., Pavic, A., Srdic-Rajic, T., Petkovic, M., Nikolic, K.
- ID
- ZDB-PUB-221224-34
- Date
- 2022
- Source
- Pharmaceutics 14(12): (Journal)
- Registered Authors
- Keywords
- 1-benzhydryl piperazine, anti-metastatic effect, breast cancer, drug discovery, histone deacetylases, hydroxamic acid, zebrafish xenograft model
- MeSH Terms
- none
- PubMed
- 36559094 Full text @ Pharmaceutics
Citation
Ruzic, D., Ellinger, B., Djokovic, N., Santibanez, J.F., Gul, S., Beljkas, M., Djuric, A., Ganesan, A., Pavic, A., Srdic-Rajic, T., Petkovic, M., Nikolic, K. (2022) Discovery of 1-Benzhydryl-Piperazine-Based HDAC Inhibitors with Anti-Breast Cancer Activity: Synthesis, Molecular Modeling, In Vitro and In Vivo Biological Evaluation. Pharmaceutics. 14(12):.
Abstract
Isoform-selective histone deacetylase (HDAC) inhibition is promoted as a rational strategy to develop safer anti-cancer drugs compared to non-selective HDAC inhibitors. Despite this presumed benefit, considerably more non-selective HDAC inhibitors have undergone clinical trials. In this report, we detail the design and discovery of potent HDAC inhibitors, with 1-benzhydryl piperazine as a surface recognition group, that differ in hydrocarbon linker. In vitro HDAC screening identified two selective HDAC6 inhibitors with nanomolar IC50 values, as well as two non-selective nanomolar HDAC inhibitors. Structure-based molecular modeling was employed to study the influence of linker chemistry of synthesized inhibitors on HDAC6 potency. The breast cancer cell lines (MDA-MB-231 and MCF-7) were used to evaluate compound-mediated in vitro anti-cancer, anti-migratory, and anti-invasive activities. Experiments on the zebrafish MDA-MB-231 xenograft model revealed that a novel non-selective HDAC inhibitor with a seven-carbon-atom linker exhibits potent anti-tumor, anti-metastatic, and anti-angiogenic effects when tested at low micromolar concentrations.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping