Colorimetric study helps identify promising therapeutics for prostate cancer
Researchers at the University of Bath (UK) have developed a test to allow structure-activity relationship studies to be carried out on a key prostate cancer protein, revealing potential inhibitor compounds.
A team at the University of Bath (UK), led by Matthew Lloyd, Senior Lecturer in the Department of Pharmacy and Pharmacology, has developed a method to systematically measure the activity of α-methylacyl-CoA racemase (AMACR), a protein overexpressed in prostate cancer. The work has allowed the team to take systematic measurements of activity suppression with different compounds, leading to the discovery of key inhibitory molecular features. This work could provide a basis for the development of novel prostate cancer therapeutics to slow progression of the disease.
AMACR has long been identified as a key protein in prostate cancer, with overexpression causing a tenfold increase in the proteins activity in affected cells. It has been thought that an increase in expression causes cancerous cells to become more aggressive, hastening their spread. However, activity levels of AMACR have proven notoriously difficult to track, which makes carrying out an effective structure-activity relationship study impossible.
In their latest work, Lloyd’s team designed a simple colorimetric test to measure AMACR activity, opening up the protein for investigation. The group analyzed 23 known and potential AMACR inhibitors in a structure-activity relationship study, identifying a potential rational for inhibition.
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Results showed that the lipophilicity of the ligand positively affected its potency, possibly due to the presence of a hydrophobic pocket in the protein. The presence of acyl-CoA esters also increased the effectiveness of the inhibitory compounds. These indicators, alongside further studies, could provide a basis for the rational design of AMACR inhibitory therapeutics to treat prostate cancer.
“This is a small but important step in the development of new treatments for prostate cancer based on AMACR inhibition. It’s important because it provides a framework with which to predict and measure drug effectiveness,” Lloyd discussed.
"This will facilitate the development of new treatments for prostate cancer and other cancers in which AMACR levels are increased.”
Notably, this project has been funded by Prostate Cancer UK (London, UK) and the Movember Foundation (UK). Matthew Hobbs, Deputy Director of Research at Prostate Cancer UK, commented: “Over 11,000 men die from prostate cancer every year in the UK, making it the third biggest cancer killer. In these men prostate cancer cells grow and evolve and eventually become resistant to the treatments currently available to combat the disease. However, important research like this which seeks to find new, innovative ways to treat prostate cancer has the potential to stop this trend.”
Yevglevskis M, Lee GL, Nathubhai A et al. Structure-activity relationships of rationally designed AMACR 1A inhibitors. Bioorg. Chem. 79, 145–154 (2018); www.bath.ac.uk/announcements/scientists-screen-molecules-for-potential-as-new-prostate-cancer-drugs/