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. 2015 Jun 4;125(23):3588-97.
doi: 10.1182/blood-2014-10-605584. Epub 2015 Mar 26.

Targeting deubiquitinase activity with a novel small-molecule inhibitor as therapy for B-cell malignancies

Luke F Peterson  1 , Hanshi Sun  1 , Yihong Liu  1 , Harish Potu  1 , Malathi Kandarpa  1 , Monika Ermann  2 , Stephen M Courtney  2 , Matthew Young  3 , Hollis D Showalter  4 , Duxin Sun  5 , Andrzej Jakubowiak  6 , Sami N Malek  1 , Moshe Talpaz  1 , Nicholas J Donato  1
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Targeting deubiquitinase activity with a novel small-molecule inhibitor as therapy for B-cell malignancies

Luke F Peterson et al. Blood. .
Free article

Abstract

Usp9x was recently shown to be highly expressed in myeloma patients with short progression-free survival and is proposed to enhance stability of the survival protein Mcl-1. In this study, we found that the partially selective Usp9x deubiquitinase inhibitor WP1130 induced apoptosis and reduced Mcl-1 protein levels. However, short hairpin RNA-mediated knockdown (KD) of Usp9x in myeloma cells resulted in transient induction of apoptosis, followed by a sustained reduction in cell growth. A compensatory upregulation of Usp24, a deubiquitinase closely related to Usp9x, in Usp9x KD cells was noted. Direct Usp24 KD resulted in marked induction of myeloma cell death that was associated with a reduction of Mcl-1. Usp24 was found to sustain myeloma cell survival and Mcl-1 regulation in the absence of Usp9x. Both Usp9x and Usp24 were expressed and activated in primary myeloma cells whereas Usp24 protein overexpression was noted in some patients with drug-refractory myeloma and other B-cell malignancies. Furthermore, we improved the drug-like properties of WP1130 and demonstrated that the novel compound EOAI3402143 dose-dependently inhibited Usp9x and Usp24 activity, increased tumor cell apoptosis, and fully blocked or regressed myeloma tumors in mice. We conclude that small-molecule Usp9x/Usp24 inhibitors may have therapeutic activity in myeloma.

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