Cystic Fibrosis Corrector Ligands Discovered in CF Human Airway Cells

DESCRIPTION (provided by applicant): In this proposed Phase I SBIR program, DiscoveryBioMed, Inc. (DBM) will continue to build upon an active project performed in collaboration with CFTR cell biologists at the University of Alabama at Birmingham and alternative rescue chloride (Cl-) channel physiologists at Johns Hopkins University School of Medicine. DBM developed a novel and simple SPQ halide-sensitive dye- and light-based HTS drug discovery program for cystic fibrosis (CF). The key platform for this CF corrector ligand (CFCL) program is a CF human bronchial epithelial cell line homozygous for the most common CF mutation, the delF508-CFTR mutation. This CF drug discovery project began during the pre-launch phase for DBM in Fall 2007. DBM and collaborators have screened almost 10,000 small molecules to date. CFCLs have fallen into two categories of ligands with therapeutic potential: (1) delF508-CFTR correctors and (2) rescue Cl- channel enhancers. Specific delF508- CFTR correctors are validated and pursued by Drs. James Collawn and Zsuzsa Bebok at UAB. Rescue Cl- channel enhancers that up-regulate secretory Cl- transport (but do not rescue delF508-CFTR biochemically) are validated by DBM and by Drs. Lihua Liang and Bill Guggino at Johns Hopkins. This CF drug discovery program is a novel, comprehensive assessment that casts a wide net to find any and all CFCLs that have efficacy in a human cell background and that may have CF therapeutic potential. Cystic fibrosis (CF) is an inherited disease of the pulmonary and gastrointestinal systems that presents in pediatric and young adult populations. Despite an improvement in the treatment of CF symptoms, the CF drug armament still lacks therapeutics that attack the root causes of CF disease. The over-arching goal of this Phase I SBIR program is that novel CF corrector ligands will be discovered on a CF human airway cell platform that will accelerate the march toward meaningful treatment for CF children and young adults. This CF Phase I SBIR program has 2 milestones. Milestone 1 will complete a small molecule screening program of 50,000 compounds to discover novel CFCLs. Hit lists and scaffolds of common atomic structure have already emerged from the hit CFCLs in both categories of delF508-CFTR correctors and rescue Cl- channel enhancers. As an extension of Milestone 1 research, DBM will perform cheminformatic analysis of potential hit compounds after each 5,000 compounds screened to inform the validation and prioritization of the hit small molecules. Milestone 2 will validate all CFCLs, differentiate the CFCLs into the two CF therapeutic categories, and assign the hit CFCLs to each pair of academic partners for further study. As an extension of Milestone 2 research, DBM will perform final detailed cheminformatics and perform medicinal chemistry on the most potent and compelling hit lead CFCLs going forward. DBM will perform a complete cell toxicity analysis as well as assess potential toxicity of the lead CFCLs on human liver, kidney and lung cell lines on standard endpoints as an in vitro prelude to planned Phase II research. The over-arching goal of this work is to identify small molecules that may eventually be transformed into new therapeutics that will rescue lose Cl- and fluid transport in the CF lung and airways to re-hydrate lung surfaces and aid impaired mucociliary clearance in CF disease. PUBLIC HEALTH RELEVANCE: Cystic fibrosis is a disease of children and young adults that causes mortality due to its progressive and debilitating lung disease. Loss of salt and fluid secretion and accelerated absorption of salt dehydrates the airways and cause sticky mucus accumulation that eventually obstructs airflow leading to pulmonary decline in CF patients. Our company, DiscoveryBioMed, Inc., seeks to use novel methods to discover CF corrector ligands that restore salt and water secretion to prevent and attenuate the development of CF lung disease. We are partnering with two pairs of CF experts to validate these critically important and potential drugs.