Invited Speaker

Small Molecule Inhibitors of the Prolactin Receptor in Breast Cancer
Nira Ben-Jonathan
USA

Prolactin (PRL) is a 25 kDa protein hormone whose main target is the breast where it exerts mitogenic and anti-apoptotic actions. We reported that PRL stimulates growth of breast cancer cells (BCC) and confers resistance against chemotherapeutic agents. Thus, there is a major incentive to develop antagonists that block the PRL receptor (PRLR) as a treatment for breast cancer. To this end, we opted to use high throughput screening (HTS) for identifying small molecule inhibitors of the PRLR. The screening strategy included the following: a) using crystallographic data of the PRLR and its ligands to screen virtual libraries of small molecules, b) selecting a set of compounds of related chemical classes and a set of chemically diverse compounds from a small molecule compound library of >250,000 compounds, c) adapting two cell-based assays (proliferation and luciferase-reporter) for HTS, d) establishing assay reproducibility, accuracy and high signal to background ratio, e) performing the HTS, with 'hits' retested to yield EC50 values, f) verification of antagonist activity of 'hits', using different PRL endpoints in BCC. In conclusion, the identification of small molecules that block the PRLR would be extremely valuable as future therapies for preventing adverse effects of PRL in breast cancer patients.