Investigating HDAC Inhibitors for Prostate Cancer Therapy
The prestigious European Journal of Medicinal Chemistry published a collaborative study led by scientist Davide Moi in affiliation with the University of Modena and Reggio Emilia, Italy. Under the title “Discovery of Potent HDAC Inhibitors for Targeting Advanced Prostate Cancer,” the article presents the findings on the potential of histone deacetylase (HDAC) inhibitors for treating advanced prostate cancer.
This research also integrated CacoReady plates to assess the in vitro permeability of the HDAC inhibitors. The results revealed promising activity against prostate cancer cells, suggesting a possible approach for future treatment strategies.
Designing innovative HDAC inhibitors targeting HDAC6 activity
Histone deacetylases (HDACs) are crucial in regulating gene expression by acetylation/deacetylation of lysine residues in histones and non-histone proteins. They are involved in various cellular processes, such as cell cycle progression, differentiation, and apoptosis. In the context of prostate cancer, HDACs are particularly interesting because they modulate the activity of the androgen receptor (AR), a key driver of prostate cancer progression and drug resistance.
The study aimed to design and synthesize new HDAC inhibitors across three distinct series, with a specific focus on HDAC6 inhibitory activity. The compounds were evaluated for their impact on aggressive prostate cancer cell proliferation, tumor selectivity, anti-migration properties, and in vitro drug-like characteristics. Among the synthesized compounds, compound 13 was identified as a promising lead due to its higher selectivity and low toxicity, making it suitable for further research.
Assessing In Vitro Permeability: the role of Caco-2 cells
Evaluating in vitro permeability with CacoReady plates was central to the study’s design. By measuring the permeability of the synthesized compounds within Caco-2 cells, researchers could identify and select which compounds were best in terms of cellular adsorption.
The results revealed variations in cell membrane permeability among the series of compounds. This observation indicated a potential trade-off between higher in vitro HDAC6 inhibitory activity and lower cell permeability. Consequently, the study concluded that optimizing the lead hydroxamic acid derivatives is necessary to strike a balance between potency and permeability.
This study provides an in-depth exploration of HDAC inhibitors in the context of advanced prostate cancer treatment. It also underscores the role of advanced cell culture products, such as MedTech Barcelona’s CacoReady plates, in evaluating drug permeability. The findings suggest that HDAC inhibitors have the potential to play an essential role in shaping future prostate cancer therapies, making this research a valuable contribution to cancer treatment strategies.
Read the full article: Moi D, Bonanni D, Belluti S, et al. Discovery of potent pyrrolo-pyrimidine and purine HDAC inhibitors for the treatment of advanced prostate cancer. Eur J Med Chem. 2023;260:115730. doi:10.1016/j.ejmech.2023.115730
