This project led to the identification of a drug-like small-molecule, called 2A2, that efficiently inhibits RNF5 ligase activity and rescue F508del-CFTR in human bronchial cells derived from CF patients. In vitro experiments demonstrated that treatment with inh-02 modulates ATG4B and paxillin, both being known RNF5 targets.
These studies point to potential use of RNF5 as a novel target for F508del-CFTR. The results underline that RNF5 is a drug target and provide evidence to support its druggability. In addition, the efficacy of the identified compound as mutant CFTR corrector in primary cells demonstrates the biological relevance of this rescue mechanism.