Spotlight on ixazomib: potential in the treatment of multiple myeloma

Abstract

Despite the significant therapeutic advances achieved with proteasome inhibitors (PIs) such as bortezomib and carfilzomib in prolonging the survival of patients with multiple myeloma, the development of drug resistance, peripheral neuropathy, and pharmacokinetic limitations continue to pose major challenges when using these compounds. Ixazomib is a second-generation PI with improved activity over other PIs. Unlike bortezomib and carfilzomib, which are administered by injection, ixazomib is the first oral PI approved by US Food and Drug Administration. This review discusses the biochemical properties, mechanisms of action, preclinical efficacy, and clinical trial results leading to the US Food and Drug Administration approval of ixazomib.

Keywords: biological mechanism; clinical trials; oral administration; proteasome inhibitor.

Figure 1

Mechanism of action of ixazomib. Notes: Ixazomib (MLN9708) administered orally as a capsule is rapidly absorbed and hydrolyzed to the biologically active form (MLN2238) when it comes in contact with aqueous plasma. Ixazomib blocks protein degradation by inhibiting the 20S catalytic subunit of the 26S proteasome. More specifically, at lower concentrations, MLN2238 inhibits the β5 chymotrypsin-like subunit, which cleaves proteins after hydrophobic residues. At high concentrations, MLN2238 inhibits the β1 caspase-like subunit and β2 trypsin-like subunit, which cleave proteins after acidic and basic residues, respectively.