ML-346 is an activator of the heat shock response that induces the expression of the heat shock proteins HSP70, HSP40, and HSP27. It induces the expression of the oxidative stress response genes HO1, GCLM, and BiP in mouse embryonic fibroblasts (MEFs) and pretreatment protects cells from severe heat shock-induced death and H2O2-induced apoptosis. It promotes folding of metastable proteins in models of conformational disease, including cellular models of Huntingtin aggregation and cystic fibrosis. It reduces aggregate formation in PC12 cells expressing human Huntingtin exon 1 containing a 74 glutamine expansion when used at a concentration of 10 μM. It also corrects trafficking of cystic fibrosis transmembrane conductance regulator proteins bearing the F508 deletion (ΔF508-CFTR) mutation carried by the majority of cystic fibrosis patients, leading to increased cell surface expression.
