Homopiperazine derivatives as a novel class of proteasome inhibitors with a unique mode of proteasome binding.

ABSTRACT: The proteasome is a proteolytic machinery that executes the degradation of polyubiquitinated proteins to maintain cellular homeostasis. Proteasome inhibition is a unique and effective way to kill cancer cells because they are sensitive to proteotoxic stress. Indeed, the proteasome inhibitor bortezomib is now indispensable for the treatment of multiple myeloma and other intractable malignancies, but is associated with patient inconvenience due to intravenous injection and emerging drug resistance. To resolve these problems, we attempted to develop orally bioavailable proteasome inhibitors with distinct mechanisms of action and identified homopiperazine derivatives (HPDs) as promising candidates. Biochemical and crystallographic studies revealed that some HPDs inhibit all three catalytic sub

SUBMITTER: Kikuchi J 

PROVIDER: S-EPMC3623906 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature