Therapeutic landscape of carfilzomib and other modulators of the ubiquitin-proteasome pathway.

Abstract

For both normal and malignant cells, the degradation of intracellular proteins must be carefully controlled to adjust the levels of important regulatory proteins and rapidly eliminate damaged or misfolded proteins before their toxic aggregates compromise the cell function or survival.1,2 The ubiquitin-proteasome pathway degrades most intracellular proteins. This complex system (Fig 1) identifies proteins intended for degradation and attaches to them chains of ubiquitin (Ub) molecules3 through a sequential system of Ub-activating enzymes, Ub-conjugating enzymes, and Ub ligases.4,5 Ubiquitinated proteins are then recognized by the 26S proteasome7 and selectively digested by its distinct (chymotrypsin-like, trypsin-like, and caspase-like) proteolytic activities.8–10