Development of selective substrate based inhibitors of ubiquitin isopeptidases

DESCRIPTION (provided by applicant): The FDA approval of the proteasome inhibitor bortezomib/VELCADE(r) for the treatment of multiple myeloma and other hematological malignancies demonstrates that the ubiquitin pathway is a promising source of new drugs for the treatment of cancer and perhaps other diseases. Bortezomib, a proteasome inhibitor, exerts a global effect and its use is thus limited by a serious toxicity profile. Efforts are underway to ind ubiquitin pathway enzyme targets acting more selectivelythan the proteasome with the aim of developing drugs with improved toxicity profiles and therapeutic indices. Among these enzymes are the ubiquitin E1 activating enzyme, E2 conjugating enzyme, E3 ligase and Deubiquitylases (DUBs). DUBs act on limited numbers of target proteins and are linked biochemically and genetically to various diseases, including cancer. These enzymes are proteases and are considered druggable, and various pharmaceutical and biotech companies, including Progenra have identified n