LAUSR

Simple Summary Unabated tumor growth, metastasis, and resistance to hormone therapy and/or to chemotherapy constitute serious impediments for combating breast cancer (BC). With the exception of targeted anti-HER2/neu therapy and combination therapies, there have been no radical changes in the standard of care for BC patients in the past two decades. In addition, there are only limited options for treating BC-derived brain metastases that cause high morbidity and mortality. This report describes the use of high throughput screening (HTS) for identifying novel small molecules that blocked the prolactin receptor (PRLR) and suppressed BC in a laboratory setting. These small molecules have a great potential to become effective therapeutics in patients with BC. Abstract Prolactin (PRL) is a protein hormone which in humans is secreted by pituitary lactotrophs as well as by many normal and malignant non-pituitary sites. Many lines of evidence demonstrate that both circulating and locally produced PRL increase breast cancer (BC) growth and metastases and confer chemoresistance. Our objective was to identify and then characterize small molecules that block the tumorigenic actions of PRL in BC. We employed three cell-based assays in high throughput screening (HTS) of 51,000 small molecules and identified two small molecule inhibitors (SMIs), named SMI-1 and SMI-6. Both compounds bound to the extracellular domain (ECD) of the PRL receptor (PRLR) at 1–3 micromolar affinity and abrogated PRL-induced breast cancer cell (BCC) invasion and malignant lymphocyte proliferation. SMI-6 effectively reduced the viability of multiple BCC types, had much lower activity against various non-malignant cells, displayed high selectivity, and showed no apparent in vitro or in vivo toxicity. In athymic nude mice, SMI-6 rapidly and dramatically suppressed the growth of PRL-expressing BC xenografts. This report represents a pre-clinical phase of developing novel anti-cancer agents with the potential to become effective therapeutics in breast cancer patients.