In cystic fibrosis
(CF), the deletion of phenylalanine 508 (F508del)
in the CF transmembrane conductance regulator (CFTR) leads to misfolding
and premature degradation of the mutant protein. These defects can
be targeted with pharmacological agents named potentiators and correctors.
During the past years, several efforts have been devoted to develop
and approve new effective molecules. However, their clinical use remains
limited, as they fail to fully restore F508del-CFTR biological function.
Indeed, the search for CFTR correctors with different and additive
mechanisms has recently increased. Among them, drugs that modulate
the CFTR proteostasis environment are particularly attractive to enhance
therapy effectiveness further. This Perspective focuses on reviewing
the recent progress in discovering CFTR proteostasis regulators, mainly
describing the design, chemical structure, and structure–activity
relationships. The opportunities, challenges, and future directions
in this emerging and promising field of research are discussed, as
well.
In cystic fibrosis (CF), deletion of phenylalanine 508 (F508del) in the CF transmembrane conductance regulator (CFTR) is associated to misfolding and defective gating of the mutant channel. One of the most promising CF drug targets is the ubiquitin ligase RNF5, which promotes F508del-CFTR degradation. Recently, the first ever reported inhibitor of RNF5 was discovered, i.e., the 1,2,4-thiadiazol-5-ylidene inh-2. Here, we designed and synthesized a series of new analogues to explore the structure−activity relationships (SAR) of this class of compounds. SAR efforts ultimately led to compound 16, which showed a greater F508del-CFTR corrector activity than inh-2, good tolerability, and no toxic side effects. Analogue 16 increased the basal level of autophagy similar to what has been described with RNF5 silencing. Furthermore, co-treatment with 16 significantly improved the F508del-CFTR rescue induced by the triple combination elexacaftor/tezacaftor/ivacaftor in CFBE41o − cells. These findings validate the 1,2,4-thiadiazolylidene scaffold for the discovery of novel RNF5 inhibitors and provide evidence to pursue this unprecedented strategy for the treatment of CF.
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