Noncompetitive modulation of the proteasome by imidazoline scaffolds overcomes bortezomib resistance and delays MM tumor growth in vivo.

ABSTRACT: Multiple myeloma (MM) is a malignant disorder of differentiated B-cells for which standard care involves the inhibition of the proteasome. All clinically used proteasome inhibitors, including the chemotherapeutic drug bortezomib, target the catalytic active sites of the proteasome and inhibit protein proteolysis by competing with substrate binding. However, nearly all (~97%) patients become intolerant or resistant to treatments within a few years, after which the average survival time is less than 1 year. We describe herein the inhibition of the human proteasome via a noncompetitive mechanism by the imidazoline scaffold, TCH-13. Consistent with a mechanism distinct from that of competitive inhibitors, TCH-013 acts additively with and overcomes resistance to bortezomib. Importantly, TCH-013

SUBMITTER: Lansdell TA 

PROVIDER: S-EPMC3600058 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature