Design and synthesis of an orally bioavailable and selective peptide epoxyketone proteasome inhibitor (PR-047)

J Med Chem. 2009 May 14;52(9):3028-38. doi: 10.1021/jm801329v.


Proteasome inhibition has been validated as a therapeutic modality in the treatment of multiple myeloma and non-Hodgkin's lymphoma. Carfilzomib, an epoxyketone currently undergoing clinical trials in malignant diseases, is a highly selective inhibitor of the chymotrypsin-like (CT-L) activity of the proteasome. A chemistry effort was initiated to discover orally bioavailable analogues of carfilzomib, which would have potential for improved dosing flexibility and patient convenience over intravenously administered agents. The lead compound, 2-Me-5-thiazole-Ser(OMe)-Ser(OMe)-Phe-ketoepoxide (58) (PR-047), selectively inhibited CT-L activity of both the constitutive proteasome (beta5) and immunoproteasome (LMP7) and demonstrated an absolute bioavailability of up to 39% in rodents and dogs. It was well tolerated with repeated oral administration at doses resulting in >80% proteasome inhibition in most tissues and elicited an antitumor response equivalent to intravenously administered carfilzomib in multiple human tumor xenograft and mouse syngeneic models. The favorable pharmacologic profile supports its further development for the treatment of malignant diseases.

MeSH terms

  • Administration, Oral
  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Biological Availability
  • Cell Line
  • Dipeptides / chemical synthesis*
  • Dipeptides / chemistry
  • Dipeptides / pharmacokinetics
  • Dipeptides / pharmacology*
  • Drug Design*
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Kinetics
  • Mice
  • Oligopeptides / chemical synthesis*
  • Oligopeptides / chemistry
  • Oligopeptides / pharmacokinetics
  • Oligopeptides / pharmacology*
  • Proteasome Inhibitors*
  • Structure-Activity Relationship
  • Substrate Specificity
  • Thiazoles / chemical synthesis*
  • Thiazoles / chemistry
  • Thiazoles / pharmacokinetics
  • Thiazoles / pharmacology*


  • 3-methoxy-2-(3-methoxy-2-((2-methyl-1,3-thiazol-5-yl)formamido)propanamido)-N-(1-(2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)propanamide
  • Antineoplastic Agents
  • Dipeptides
  • Enzyme Inhibitors
  • Oligopeptides
  • Proteasome Inhibitors
  • Thiazoles
  • carfilzomib