Progressive renal disease remains an unsolved challenge for the nephrologist, as it almost inevitably leads to end-stage renal failure, a life-threatening condition that necessitates renal replacement therapy. Few, if any, of the currently practiced therapeutic strategies oppose the molecular and cellular programs of apoptosis and fibrosis that drive renal disease. Scatter factor/hepatocyte growth factor (SF/HGF), is a renotrophic factor with anti-apoptotic and anti-fibrotic properties. However clinical feasibility of SF/HGF administration as gene or protein therapy is limited by issues relating to the immune and inflammatory responses evoked by adenoviral proteins, inherent instability of proteins in solution, their limited tissue half-life and exorbitant costs. Using a drug-discovery engine comprising 3-dimensional molecular modeling, phage display, rational drug design, targeted proteomics and in vitro biology, Angion Biomedica Corp. has identified two, chemically distinct, small molecules that activate the SF/HGF receptor c-Met. These drug candidates activate the SF/HGF/c-Met signaling cascade, and exert cytoprotective and anti-fibrotic effects in vitro. Preliminary data in an in vivo model of progressive renal disease indicate that these small molecule SF/HGF mimetics oppose interstitial collagen deposition and preserve renal function. Preliminary data from regulatory safety studies suggest that these chemical class members are safe and well-tolerated. Using rational drug-design based chemical substitutions, we have now constructed structural libraries around these small molecules. The goal of this Phase I application is to couple in vitro targeted proteomics to in vivo bioefficacy studies in order to identify a lead SF/HGF mimetic within each chemical class, with the eventual goal of bringing an SF/HGF mimetic to clinical trials for the treatment of progressive renal disease. A small molecule anti-fibrotic has significant clinical potential for the treatment of progressive renal disease. ? ? ?
