Novel molecular therapeutics for cystic fibrosis

DESCRIPTION provided by applicant Cystic fibrosis CF leads to chronic illness disability and early death Recurrent pulmonary infections are lethal owing to growth of bacteria and other microorganisms in the abnormally viscous mucus Antibiotics mucolytics and anti inflammatory agents are useful only in treating some CF effects Recently however ivacaftor a k a VX or Kalydeco which addresses the underlying cause of CF was approved by the FDA Unfortunately it is ineffective in a majority of patients The underlying cause of CF is a mutatio of the cystic fibrosis transmembrane conductance regulator CFTR which normally localizes to the cell membrane and controls salt levels In CF a mutation decreases the amount or activity of CFTR and the resultant salt dysregulation leads to CF pathologies The primary mutation andgt in the US and worldwide is F deletion of a single phenylalanine residue in CFTR F causes improper folding of CFTR most of which is degraded in the endoplasmic reticulum ER and does not reach the cell membrane CFTR F is partially functional if it can be localized to the membrane and andquot correctorandquot drugs such as VX lumacaftor are being developed to promote trafficking of mutant CFTR to the cell surface Additional ways of increasing the levels trafficking and or functionality of CFTR F are being sought by intervening in various cellular pathways that regulate proteins including the ubiquitin proteasome pathway Misfolded CFTR F is ubiquitylated by the ubiquitin E ligase gp and degraded via ERAD endoplasmic reticulum associated protein degradation decreasing its cellular level Knockdown of gp leads to dramatically increased levels of CFTR F in cells and increases chloride transport Thus gp inhibition should increase the amount of CFTR at the cell surface and may be useful alone or combined with correctors such as VX In phase I small molecule inhibitors of gp were identified and their ability to increase levels of functional CFTR as judged by cellular assays demonstrated One of these hits GP increased the level of core glycosylated CFTR F and when combined with VX increased the level of functional CFTR F in cells providing further validation of gp as a target for the treatment of CF In Phase II GP and additional hit compounds will be improved by medicinal chemistry optimization analyzed by in vitro and cell based secondary assays and tested in animal models for drug metabolism pharmacokinetic properties with the goal of identifying potent and selective lead compounds with efficacy as therapeutic agents for cystic fibrosis PUBLIC HEALTH RELEVANCE A salt regulating membrane protein CFTR is mutated in cystic fibrosis producing its symptoms the mutated protein has partial activity but because it is misfolded it is largely degraded in the cell The proposed Phase II project entails the preclinical development of small molecule inhibitors of gp an enzyme responsible for the degradation of mutated CFTR These inhibitors were identified and characterized in Phase I one of them in particular was shown to exert the predicted therapeutic effects in cell models