Homopiperazine Derivatives as a Novel Class of Proteasome Inhibitors with a Unique Mode of Proteasome Binding

Jiro Kikuchi,Tohru Izumi,Masaharu Nobuyoshi,Miyuki Akutsu,Naoya Shibayama,Yasuhiko Kano,Satoshi Yamada,Yusuke Furukawa,Sam-Yong Park,Taeko Wada,Mio Ohki,Kanako Sugiyama,Andrea Cavalli

doi:10.1371/journal.pone.0060649

Jiro Kikuchi, Tohru Izumi + Show 11 more

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https://doi.org/10.1371/journal.pone.0060649

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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 subunits (ß 1, ß 2 and ß 5) of the proteasome by direct binding, whereas bortezomib and other proteasome inhibitors mainly act on the ß5 subunit. Proteasome-inhibitory HPDs exhibited cytotoxic effects on cell lines from various hematological malignancies including myeloma. Furthermore, K-7174, one of the HPDs, was able to inhibit the growth of bortezomib-resistant myeloma cells carrying a ß5-subunit mutation. Finally, K-7174 had additive effects with bortezomib on proteasome inhibition and apoptosis induction in myeloma cells. Taken together, HPDs could be a new class of proteasome inhibitors, which compensate for the weak points of conventional ones and overcome the resistance to bortezomib.

Highlights

The paradigm of cancer treatment has been dramatically changed by the introduction of small molecular compounds that target the ‘‘Achilles’ heel’’ of cancer cells [1]
We show that homopiperazine derivatives (HPDs) constitute a novel class of proteasome inhibitor (PI) with a unique mode of proteasome binding
Many kinds of small molecular PIs with various chemical structures have been developed [40,41], this is the first demonstration of the proteasome-inhibitory activity of HPDs

Summary

Introduction

The paradigm of cancer treatment has been dramatically changed by the introduction of small molecular compounds that target the ‘‘Achilles’ heel’’ of cancer cells [1]. Cancer cells are very sensitive to proteotoxic stress because of intracellular protein overload due to rapid cell cycling and apoptosis inhibition This feature makes proteasome inhibition a unique and effective way to kill cancer cells that can tolerate conventional therapies [3]. Bortezomib is the first proteasome inhibitor (PI) approved for clinical application, which preferentially targets ß1 and ß5 subunits of the proteasome [3,4] This drug is effective for multiple myeloma (MM), because it accelerates the unfolded protein response (UPR) via down-regulation of histone deacetylases (HDACs) [5,6] and targets cell adhesion-mediated drug resistance via down-regulation of very late antigen-4 [7,8]. Bortezomib is indispensable for the treatment of MM in combination with other anti-cancer drugs including alkylating agents, corticosteroids and HDAC inhibitors [9,10,11]

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