Currently approved drug-eluting stents are plagued by late-stage thrombosis and delayed restenosis. Acceleration of stent re-endothelialization can suppress neointimal hyperplasia, promote healing of the vessel wall, and decrease restenosis rates. Scatter factor/hepatocyte growth factor (SF/HGF) promotes endothelial cell proliferation and migration. Feasibility of using an SF/HGF coat as an adjuvant on drug-eluting stents is compounded by issues relating to gene and protein therapy. Angion Biomedica is pursuing the development of small molecules that regulate SF/HGF/c-Met signaling to therapeutic advantage. Based on the 3-dimensional structure of the ATP-binding site of the SF/HGF receptor c-Met's tyrosine kinase domain and using a product discovery engine comprising phage display, 3-dimensional molecular modeling, protein chemistry and preclinical biology, we have identified a phthalazin-1 (2H)-one scaffold with potential SF/HGF-like bioactivity. Rational drug design-driven side-chain additions onto this scaffold led to the identification of Ang 1170, the first small molecule drug-like member within this class. Preliminary data indicate that Ang 1170 activates the SF/HGF/c-Met pathway, stimulates endothelial cell proliferation, and protects against endothelial cell death. Importantly, Ang 1170 has no effects on fibroblast or vascular smooth muscle cell proliferation. We have since constructed a structural library around the phthalazin-1 (2H)-one scaffold comprising 21 compounds with potential SF/HGF-like bioactivity, the eventual goal being the identification of an SF/HGF-like small molecule that is not only bioeffiacious and potent but also carries a safety profile compatible with human use. The goal of this Phase I application is to couple targeted proteomics and medicinal chemistry to an in vivo bioefficacy assay in order to identify lead and fallback candidates within this phthalazin-1 (2H)-one library for stimulation of the endothelial cell proliferation program. The two candidates emerging from this Phase I program will then be submitted to in-depth, preclinical SBIR Phase II studies comprising in vivo models of in-stent restenosis, biodistribution studies, and formal regulatory/safety studies. The ultimate goal of this study is to advance an SF/HGF-like small molecule to the clinic for use as an adjuvant coat on currently used drug-eluting stents.Late stage thrombosis and delayed restenosis plague currently approved drug-eluting stents and remains a significant cause of morbidity and mortality. A small molecule therapeutic that reduces restenosis has tremendous clinical benefit. ? ? ?
