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

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.

• Authors: Luke F Peterson, Hanshi Sun, Yihong Liu, Harish Potu, Malathi Kandarpa, Monika Ermann, Stephen M Courtney, Matthew Young, Hollis D Showalter, Duxin Sun, Andrzej Jakubowiak, Sami N Malek, Moshe Talpaz, Nicholas J Donato
• Journal: Blood (Blood) Vol. 125 Issue 23 Pg. 3588-97 (Jun 04 2015) ISSN: 1528-0020 [Electronic] United States
• PMID: 25814533 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 by The American Society of Hematology.

Chemical References

• Cyanoacrylates
• Enzyme Inhibitors
• MCL1 protein, human
• Myeloid Cell Leukemia Sequence 1 Protein
• Pyridines
• USP24 protein, human
• USP9X protein, human
• degrasyn
• Ubiquitin Thiolesterase

Topics

• Animals
• Apoptosis (drug effects, genetics)
• Cell Line, Tumor
• Cyanoacrylates (pharmacology)
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (pharmacology)
• Female
• Gene Expression Regulation, Enzymologic (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Lymphoma, Mantle-Cell (drug therapy, enzymology, genetics, pathology)
• Male
• Mice
• Multiple Myeloma (drug therapy, enzymology, genetics, pathology)
• Myeloid Cell Leukemia Sequence 1 Protein (genetics, metabolism)
• Pyridines (pharmacology)
• Ubiquitin Thiolesterase (antagonists & inhibitors, genetics, metabolism)