High-Throughput Screening Used to Identify Promising Prostate Cancer Treatments

A team from the University of Bath has recently used high-throughput screening techniques to evaluate tens of thousands of compounds to identify promising prostate cancer drugs. These researchers, from the University’s Departments of Chemistry and Pharmacy & Pharmacology, are analyzing the α-methylacyl-CoA racemase (AMACR) protein as a possible target for cancer drugs.

This protein’s expression can be increased ten times in prostate cancer, making researchers hopeful that it could be a powerful target for therapeutic agents. Previous research has shown that reducing levels of AMACR could make cancer cells behave less aggressively like normal cells. This new study, published in Bioorganic Chemistry has leveraged technology to identify several molecules that could potentially serve to lower the expression of this protein.

“Although previously identified drugs are very effective in laboratory tests, in practice they are difficult to use in therapies because their properties do not allow easy distribution throughout the body,” explained lead author Dr. Matthew Lloyd, Department of Pharmacy & Pharmacology at the University. “We started this study because we wanted to identify drugs which would be easier to use therapeutically. Although the particular compounds identified in this study did not kill prostate cancer cells very effectively, it is very promising that drug-like molecules were identified.”

Background of the University of Bath Study

In this work, a technique developed at the University of Bath was used to test over 20,000 drug-like molecules for their ability to inhibit AMACR. This high-throughput screening technology uses a simple color-change technique to allow for rapid assessment of active compounds and recognition of new drug types. This was used to classify drugs that can effectively inhibit AMACR in a novel manner.

This novel assay for AMACR was based on the elimination of 2,4-dinitrophenolate and was created to screen a total of 20,387 drug-like compounds. The rate of throughput was 768 compounds per day. The team identified pyrazoloquinolines and pyrazolopyrimidines to be “novel scaffolds” and were studied as inhibitors of AMACR.

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“This is the first report of the identification of specific drug-like small-molecule AMACR inhibitors by high-throughput screening. Pyrazoloquinolines and pyrazolopyrimidines may also be useful as inhibitors of other CoA-utilizing enzymes,” the authors concluded.

The Need for Prostate Cancer Treatments

With over 47,000 new cases reported in 2015 and over 11,000 deaths in 2014, prostate cancer is the most common male-specific cancer in the UK. The disease accounts for 26% of all cancers in men, with the risk of developing prostate cancer being one in eight for every man. 84% of men with prostate cancer will live for 10 or more years with the condition, however, the need for new treatments is imperative in combatting the disease.

“With one man dying from prostate cancer every 45 minutes in the UK there is a desperate need to develop new and effective treatments for the disease, and that’s why it’s so important that we continue to fund explorative studies like this,” said Simon Grieveson, Head of Research Funding at Prostate Cancer UK. “The protein AMACR has been shown to be present in larger quantities in aggressive prostate cancer cells, and this research group has successfully developed a technique to find the protein and monitor its activity. Further to this, they have now found certain compounds that can target this protein’s activity in the lab, and stop the cancer cells in their tracks. The research is still in its infancy and is some way off from clinical investigation, however, this is certainly promising and we look forward to seeing how this research progresses over the coming years.”