An Historic Perspective of Proteasome Inhibition Dixie-Lee Esseltine* and George Mulligan † The ubiquitin–proteasome system (UPS) and associated signaling pathways are regarded today as an exciting area of development for novel therapeutics. However, two decades ago, following the discovery and elucidation of ubiquitin and the 26S proteasome as key mediators of protein turnover, the concept of inhibiting the UPS was not even considered a feasible therapeutic approach due to the assumption that inhibition of this pathway would have widespread deleterious effects. Subsequent clinical developments with the first-in-class proteasome inhibitor bortezomib have radically overturned that view, with the proteasome now recognized as a validated target and proteasome inhibition demonstrated to be a highly successful treatment for a number of hemato- logic malignancies. Here we provide a historic perspective on the emergence of proteasome inhibition, sharing some of the lessons learned along the way. We describe the development of bortezomib and the elucidation of the effects of its novel mechanism of action, and place the cutting-edge work described elsewhere in this issue in the context of these historic developments. Semin Hematol 49:196 –206. © 2012 Elsevier Inc. All rights reserved. I n the past two decades, perceptions have radically shifted, from the proteasome being seen as essen- tial to the homeostasis of all cells and, thus, an undruggable target, to the ubiquitin–proteasome sys- tem (UPS) now regarded as an exciting area for devel- opment of novel therapeutics. Associated with this shift in perception, the scientific and clinical landscape of anti-cancer therapy has also fundamentally changed, with the emergence of pathway-specific targeted agents and the concept of personalized medicine based on spe- cific disease characteristics. 1 In the particular field of multiple myeloma (MM), the progress towards developing more effective treatment has been revolutionary. The widespread use of protea- some inhibitors and immunomodulatory drugs 2,3 has led to a substantial improvement in outcomes com- pared with the median survival plateau that had existed since the introduction of melphalan-prednisone more than 40 years ago. 4 Proteasome inhibitors have also had a substantial impact in the related plasma cell dyscra- sias, such as systemic amyloidosis, 5 and in subtypes of non-Hodgkin lymphoma including Waldenström’s mac- roglobulinemia. 6,7 Furthermore, there has been an in- creased understanding of the molecular and genetic basis of cancer and other diseases in tandem. Our understanding of the complex signaling pathways af- fected by proteasome inhibition continues to grow, 8 opening up new areas of potential exploration for the use of proteasome inhibitors and aiding the identifica- tion and development of rational combination ap- proaches to therapy. This review provides the historic perspective on the emergence of proteasome inhibition as an important therapeutic approach in hematologic malignancies and beyond, sharing some of the lessons learned along the way. We describe the development of the first-in-class agent bortezomib and the elucidation of the effects of its novel mechanism of action, and place the cutting- edge work described elsewhere in this special issue in the context of these historic developments. INHIBITING THE WHAT?—PROTEIN QUALITY CONTROL WITHIN THE CELL The Discovery of the UPS The first critical step towards considering protea- some inhibition as a therapeutic approach was the discovery of the UPS 9 and the elucidation of its func- tions. Aaron Ciechanover, Avram Hershko, and Irwin Rose were awarded the Nobel Prize in Chemistry in *Oncology Clinical Research, Millennium Pharmaceuticals, Inc, Cam- bridge, MA. †Translational Medicine, Millennium Pharmaceuticals, Inc, Cam- bridge, MA. Conflicts of interests: D.-L.E., G.M.: Employment with Millennium Pharmaceuticals, Inc., manufacturer of bortezomib (Velcade), and developer of the newer-generation proteasome inhibitor MLN9708 and the NEDD8-activating enzyme inhibitor MLN4924. Address correspondence to Dixie-Lee Esseltine, MD, Millennium Phar- maceuticals, Inc, 40 Landsdowne St, ambridge, MA 02139. E-mail: dixie-lee.esseltine@mpi.com; or George Mulligan, PhD, Millennium Pharmaceuticals, Inc, 35 Landsdowne St, Cambridge, MA 02139. E-mail: george.mulligan@mpi.com. 0037-1963/$ - see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1053/j.seminhematol.2012.04.009 Seminars in Hematology, Vol 49, No 3, July 2012, pp 196 –206 196