Bortezomib's scientific origins and its tortuous path to the clinic

Abstract

The development of bortezomib for the treatment of multiple myeloma was made possible by multiple major advances in our understanding of intracellular protein breakdown. The primary route for degradation of intracellular proteins is the ubiquitin-proteasome pathway, in which protein substrates are linked to ubiquitin chains, which marks them for degradation by the large proteolytic complex, the 26S proteasome. It utilizes ATP to unfold protein substrates and inject them into the 20S proteasome where proteins are digested to small peptides. Its active sites cleave proteins by an unusual mechanism that allows their selective inhibition by bortezomib. This molecule was generated by a small biotechnology company whose initial goal was to synthesize proteasome inhibitors to reduce the excessive proteolysis that causes muscle atrophy and cachexia. However, the availability of proteasome inhibitors suggested other therapeutic possibilities; for example, its role in the activation of the NF-κB suggested anti-inflammatory and antineoplasticactions and led to clinical trials against various cancers. Indications of the special sensitivity of multiple myeloma were observed in Phase I trials, and bortezomib was initially approved after only Phase II trials. In myeloma cells, NF-κB isparticularly important for cell growth, but bortezomib has multiple antineoplastic actions, especially its ability to inhibit the selective degradation of misfolded proteins, and myeloma cells are continually generating such abnormal immunoglobins. Although its development was unusually rapid, these efforts encountered many obstacles, and several times were almost terminated. Beyond their major clinical impact, proteasome inhibitors are extremely useful research tools and have enabled enormous advances in our understanding of cell regulation, immune mechanisms, and disease. © Springer Basel AG 2011.