Proteasome Inhibition in Multiple Myeloma: Head-to-Head Comparison of Currently Available Proteasome Inhibitors

Cell Chem Biol. 2019 Mar 21;26(3):340-351.e3. doi: 10.1016/j.chembiol.2018.11.007. Epub 2019 Jan 3.


Proteasome inhibitors (PIs) are a backbone of multiple myeloma (MM) therapy. The proteasome harbors six proteolytically active subunits (β1, β2, β5), while β5 was identified as rate-limiting and is a primary target of clinically available PIs. The most effective pattern of subunit inhibition provided by these PIs for cytotoxic activity in MM is unknown. A head-to-head comparison of clinically available PIs shows that in the clinically relevant setting only the co-inhibition of β1 or β2 with β5 activity achieves meaningful functional proteasome inhibition and cytotoxicity, while the selective β2/β5 inhibition of both constitutive and immunoproteasome is the most cytotoxic. In the long-term setting, selective inhibition of β5 subunit is sufficient to induce cytotoxicity in PI-sensitive, but not in PI-resistant MM, and the β5/β2 co-inhibition is the most cytotoxic in PI-resistant MM. These results give a rational basis for selecting individual PIs for the treatment of MM.

Keywords: activity-based probes; bortezomib; carfilzomib; multiple myeloma; proteasome; proteasome inhibitors; resistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / metabolism*
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Apoptosis / drug effects
  • Bortezomib / metabolism
  • Bortezomib / pharmacology
  • Bortezomib / therapeutic use
  • Drug Resistance, Neoplasm / drug effects
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Middle Aged
  • Multiple Myeloma / drug therapy
  • Multiple Myeloma / metabolism
  • Multiple Myeloma / pathology
  • Oligopeptides / metabolism
  • Oligopeptides / pharmacology
  • Oligopeptides / therapeutic use
  • Proteasome Endopeptidase Complex / chemistry
  • Proteasome Endopeptidase Complex / metabolism*
  • Proteasome Inhibitors / metabolism*
  • Proteasome Inhibitors / pharmacology
  • Proteasome Inhibitors / therapeutic use
  • Protein Subunits / antagonists & inhibitors
  • Protein Subunits / metabolism
  • Tissue Distribution
  • Tumor Cells, Cultured


  • Antineoplastic Agents
  • Oligopeptides
  • Proteasome Inhibitors
  • Protein Subunits
  • Bortezomib
  • carfilzomib
  • Proteasome Endopeptidase Complex