FIG. 10.

Thioredoxin: A redox target for anticancer intervention. The small redox protein thioredoxin (Trx-1) is an important cancer drug target for redox chemotherapeutic intervention. Akyl-2-imidazolyl disulfides including the investigational drug PX-12 (58) inactivate thioredoxin by disulfide exchange leading to thioalkylation of a critical cysteine residue (Cys73) or oxidative formation of a disulfide bridge between Cys32 and Cys35. PMX464 (59) is an electrophilic double-Michael pharmacophore containing 4-hydroxycyclohexa-2,5-dien-1-one that targets cysteine residues 32 and 35 of the thioredoxin active site, potentially through dual Michael adduction.