This project is to develop small non-peptide molecules that mimic the structures and functions of a novel bradykinin antagonist dimer B201 and kill human, lung cancer cells specifically and effectively via a unique "biased-agonist" mechanism. "Biased-agonists" are receptor-mediated and inhibit the growth of lung cancer cells by inducing apoptotic cell death. Our lead compounds are derived from the clues of our bradykinin antagonist dimeric structures and from some reported structures for non- peptide bradykinin antagonists. We have introduced several drastic and novel modifications and have identified the unique structures of some pharmacophores consisting of a hydrophobic core and positively charged bulky terminal groups. Preliminary studies demonstrated their potential efficacy in killing lung cancer cells in vitro and in vivo. Pronounced apoptosis was induced when cancer cells were treated with these new mimetics. Compared to B201, these new mimetic compounds are cheaper to synthesize, more stable, good bioavailability and solubility, high receptor affinity and selectivity, and most importantly, they kill lung cancer cells quite effectively. This phase I project is to further optimize our lead compounds, to improve their specificity and potency, to further establish their in vivo therapeutic efficacy and to select a lead compound for future Phase II development. PROPOSED COMMERCIAL APPLICATIONS: There are no good therapies available for the treatment of human lung cancers. This is the first report of potent small molecules that mimic novel bradykinin antagonist dimer and kill lung cancer cells specifically and effectively via a unique "biased-agonist" mechanism. "Biased-agonists" are receptor-mediated and inhibit the growth of lung cancer cells by inducing apoptotic cell death. These non-peptide molecules can easily be developed as potential therapeutics for lung cancers.
