title: 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: Department of Internal Medicine/Division of Hematology/Oncology, University of Michigan School of Medicine and Comprehensive Cancer Center, Ann Arbor, MI;
authors: Luke F
authors: LF
authors: Peterson
authors: Department of Internal Medicine/Division of Hematology/Oncology, University of Michigan School of Medicine and Comprehensive Cancer Center, Ann Arbor, MI;
authors: Hanshi
authors: H
authors: Sun
authors: Department of Internal Medicine/Division of Hematology/Oncology, University of Michigan School of Medicine and Comprehensive Cancer Center, Ann Arbor, MI;
authors: Yihong
authors: Y
authors: Liu
authors: Department of Internal Medicine/Division of Hematology/Oncology, University of Michigan School of Medicine and Comprehensive Cancer Center, Ann Arbor, MI;
authors: Harish
authors: H
authors: Potu
authors: Department of Internal Medicine/Division of Hematology/Oncology, University of Michigan School of Medicine and Comprehensive Cancer Center, Ann Arbor, MI;
authors: Malathi
authors: M
authors: Kandarpa
authors: Department of Drug Discovery Alliance, Evotec, Abingdon, Oxfordshire, United Kingdom;
authors: Monika
authors: M
authors: Ermann
authors: Department of Drug Discovery Alliance, Evotec, Abingdon, Oxfordshire, United Kingdom;
authors: Stephen M
authors: SM
authors: Courtney
authors: Department of Pharmacology, University of Michigan School of Medicine and Comprehensive Cancer Center, Ann Arbor, MI;
authors: Matthew
authors: M
authors: Young
authors: Department of Medicinal Chemistry and.
authors: Hollis D
authors: HD
authors: Showalter
authors: Department of Pharmaceutical Sciences, University of Michigan College of Pharmacy, Ann Arbor, MI; and.
authors: Duxin
authors: D
authors: Sun
authors: Section of Hematology/Oncology, University of Chicago Medical Center, Chicago, IL.
authors: Andrzej
authors: A
authors: Jakubowiak
authors: Department of Internal Medicine/Division of Hematology/Oncology, University of Michigan School of Medicine and Comprehensive Cancer Center, Ann Arbor, MI;
authors: Sami N
authors: SN
authors: Malek
authors: Department of Internal Medicine/Division of Hematology/Oncology, University of Michigan School of Medicine and Comprehensive Cancer Center, Ann Arbor, MI;
authors: Moshe
authors: M
authors: Talpaz
authors: Department of Internal Medicine/Division of Hematology/Oncology, University of Michigan School of Medicine and Comprehensive Cancer Center, Ann Arbor, MI;
authors: Nicholas J
authors: NJ
authors: Donato
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D045744:Cell Line, Tumor; D003487:Cyanoacrylates / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D043222:Ubiquitin Thiolesterase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D003487:Cyanoacrylates; D004791:Enzyme Inhibitors; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011725:Pyridines; C513810:USP24 protein, human; C506234:USP9X protein, human; C519751:degrasyn; D043222:Ubiquitin Thiolesterase