Synthetic IDE inhibitors sensitize and reverse acquired resistance of multiple myeloma cells to proteasome inhibitors

The use of proteasome inhibitors (PIs) is the backbone of multiple myeloma (MM) treatment. However, almost all MM patients who initially respond to PIs eventually develop resistance to these drugs. The discovery of a pharmacological intervention that increase the potency of PIs in order to reduce their dose and/or restore the sensitivity of MM cells to PIs is an important avenue in MM research. Insulin Degrading Enzyme (IDE) is a druggable protease known to modulate proteasome. We show here that, in two independent cohorts, a high expression of IDE in cells from MM patients is associated with shorter overall survival. Likewise, we designed specific, cell permeable, IDE inihibitors and showed that full pharmacological engagement of IDE is associated with enhanced sensitivity to PIs of MM cell lines, as well as of primary patient MM cells. Furthermore, treatment of PI-resistant MM cells with the inhibitor overcomes their resistance to PI. Finally we designed an improved IDE inhibitor suitable for in vivo pharmacology. This inhibitor which develops multiple interactions with IDE at the catalytic site and display good pharmacocinetic properties, boosts the anti-myeloma potency of bortezomib in a syngenic mouse model of MM. In vitro, it appears that IDE inhibition reduces the residual proteasome activty in PI-treated cells and increases the apoptotic potency of carfilzomib through induction of an Integrated Stress Response associated with strongly reduced IGF1 and IGF1R expressions. The pharmacological profile of this new combination appears highly desirable for the treatment of MM. Overall design: Total RNA of HeLa cells treated with DMSO, 20nM carfilzomib (CFZ), 15µM of compound 1a (CPD 1a) or the combination of these two compounds for 8h or 24h was extracted using the NucleoSpin® RNA extraction (Macherey-Nagel, Hoerdt, France). Total RNA of HeLa cells at the time of treatment (0h) was also extracted. The experiment was repeated 4 times.