The Ubiquitin-Proteasome System as a Target for Drug Development

2 The Ubiquitin-Proteasome System as a Target for Drug Development 

These mechanistic findings supported the exploration of the therapeutic potential of proteasome inhibitors in oncology, with the first clinical trials involving a proteasome inhibitor (bortezomib) commencing about ten years ago. Lessons learned from bench to bedside during this time period have recently been reviewed.19 

In terms of structure and function, the 265 proteasome is an ATP-dependent multicatalytic enzyme complex comprising one or two 195 regulatory caps and a proteolytic 205 core particle within which protein degradation occurs.18,25,26 The 205 proteasome contains three pairs of proteolytic subunits, (35, (32 and (31, for which chymotrypsin-like (CT-L), trypsin-like (T-L) and caspase-like (C-L) activities have been ascribed, respectively, based on their substrate preferences.27 

The structure of NPI-0052 offered unique substitutions about the y-lactam-(3-lactone ring system with functional groups that significantly enhanced its potency and potential for drug development, as highlighted in this account. 

Structural biology provided further confirmation of the molecular target. The crystal structure of NPI-0052 in complex with the yeast 205 proteasome showed that the molecule occupies the active sites of all three pairs of proteolytic subunits (vide infra).15 

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