*10.4. E1, E2, E3 Inhibitors*

Most UPS-associated inhibitors block a specific upstream component, such as E1, E2, E3, or DUBs. Those inhibitors have proved to be successful anticancer drugs, some of which are currently in clinical trials. However, E3, the last enzyme in the ubiquitin cascade, which is responsible for transferring Ub to the substrate protein, is more specific than E1 and E2, and thus an excellent target. A nutlin inhibitor of MDM2-p53, an LCL161 inhibitor of XIAP, and an ALRN6924 inhibitor of MDM2-p53 are some of the E3 enzyme inhibitors currently in clinical trials [136]. Blocking the E3 ligase with specific inhibitors will block the ubiquitination and eventual degradation of the substrate protein, which is exactly what is needed to treat enzyme deficiencies caused by the rapid degradation of functional but misfolded proteins.
