Project: Getting around drug resistance in prostate cancer
Challenge Space
Health - Resistance
Prinicipal Investigator(s) and team names
Dr Darren Fayne, Abdirahman Ali, Molecular Design Group, School of Chemical Sciences and DCU Life Sciences Institute (LSI)
Collaborating Institutions
Funding support
Project start date
September 2025
End date
Current
Problem
Prostate cancer is one of the most common cancers in men, and standard hormone therapy works by blocking a single pocket on the androgen receptor, the protein the tumour depends on for growth. Because every available drug competes for that same pocket, a change in the pocket disables all of them at once. That is what happens in castration-resistant prostate cancer: the treatment stops working and the options run out together.
Background
The group's response has been to stop competing for that pocket.
Using computational screening of large compound collections, we identified molecules that block the androgen receptor by binding elsewhere on the protein, at a surface the receptor uses to recruit its partners. These were confirmed experimentally as antagonists that do not act through the classical route, described across three publications and protected by a patent. Because the mutations that drive resistance sit in the classical pocket, compounds working elsewhere should remain effective when conventional therapy has failed.
Solution
The current phase, supported by a DCU PhD scholarship, extends this to the receptor's DNA-binding region, the part that ultimately switches genes on and the last common step in the pathway.
Molecular dynamics simulation is used to understand how that region moves and which of its surfaces a small molecule could realistically hold, and virtual screening then searches for compounds that fit.
The wider aim is a set of chemically distinct starting points that act at different places on the same receptor, so that resistance to one does not mean resistance to all. Clinical input comes from collaborators in histopathology.