Aminopeptidase inhibition as a targeted treatment strategy in myeloma

Myeloma cells rely heavily on the unfolded protein response (UPR) to properly fold immunoglobulins. Targeting protein handling within these cells by inhibiting the aminopeptidase enzyme system—responsible for hydrolyzing amino acids from the NH2 terminus of proteins—offers a promising therapeutic strategy. CHR-2797, a novel aminopeptidase inhibitor, has been shown to suppress myeloma cell proliferation, induce growth arrest, and trigger apoptosis, even in cells resistant to conventional chemotherapies. Importantly, CHR-2797 causes minimal inhibition of bone marrow stromal cell (BMSC) proliferation but effectively overcomes the protective effects of the CHR2797 microenvironment. It inhibits myeloma cell proliferation in BMSC-bound cultures and reduces the increase in vascular endothelial growth factor (VEGF) levels typically observed when myeloma cells interact with BMSCs. Furthermore, CHR-2797 demonstrates additive and synergistic effects when combined with bortezomib, melphalan, and dexamethasone. Apoptosis occurs through both caspase-dependent and caspase-independent mechanisms, with increased expression of Noxa, Mcl-1 cleavage, and activation of the UPR. Additionally, autophagy is observed in treated cells. CHR-2797 also upregulates genes involved in the proteasome/ubiquitin pathway, as well as aminopeptidases and genes related to the amino acid deprivation response. In summary, inhibiting protein turnover through the aminopeptidase inhibitor CHR-2797 induces apoptosis in myeloma cells and represents a novel therapeutic approach that warrants further clinical investigation.