Klaus Podar^1,2 and Kenneth C. Anderson¹

¹Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, LeBow Institute for Myeloma Therapeutics; and Harvard Medical School, Boston, Massachusetts 02115, USA. ²National Center for Tumor Diseases, Department of Medical Oncology, University of Heidelberg, Germany.

Abstract

The ubiquitin-proteasome-degradation system plays a key role in multiple cellular functions. Its deregulation is associated with the initiation and progression of human diseases including not only solid and hematologic malignancies but also neurologic and autoimmune disorders. This article discusses several novel mechanistic aspects of the ubiquitin-proteasome system. Moreover, it focuses on the development, mechanisms of action, and clinical experience with Bortezomib, the first in-class-proteasome inhibitor to enter the clinics. Finally, it summarizes novel approaches to specifically target distinct components within the highly complex and dynamic ubiquitin-proteasome machinery to ultimately further increase drug activity, as well as reduce drug resistance and adverse side effects.