A Dock‐Derived PEDF Mimic Targeting Laminin Receptor Recapitulates PEDF Signaling

Pigment epithelium derived factor (PEDF) is regarded as an exceptionally potent inhibitor of angiogenesis. Our lab and others have used PEDF as a novel prostate cancer therapy, as PEDF inhibits tumor establishment, vascularization, and alters malignant signaling. PEDF has been identified as a binding partner for the cancer associated protein Laminin Receptor (LAMR1). LAMR1 overexpression is common in a variety of cancers including breast, colon, and prostate. Recently, we attempted to mimic the protein‐protein interaction between PEDF and LAMR1 using a structure based drug design approach. From our 14,000 compound screen, we identified a hit compound with anti‐proliferative capacity against several prostate cancer cell lines. We tested this hit compound in a medium‐throughput wound healing assay using the program tscratch and explored mechanisms of action at the molecular level. Cell pellets from treated and untreated prostate cancer cells were submitted for proteomic analysis using an Orbitrap Fusion and a label free quantitative approach coupled with MaxQuant and Perseus analysis. Significantly changed proteins were analyzed at the pathway level using Ingenuity Pathway Analysis. High doses of our hit compound were able to markedly reduce wound‐healing in a scratch based assay. This compound also elicits proteome wide changes to metabolic, proliferation, and genome maintenance systems. Most notably, a 10 uM dose of hit compound was able to active P53 associated pathways while inactivating MYC associated pathways. We will orthogonally validate our results using western blotting and confirm biochemical binding of our lead compound to LAMR1 in a scalable binding assay. Support or Funding Information CTSI Core Grant Purdue Cancer Research Center Department of Basic Medical Sciences