Targeting deubiquitinase activity with a novel small-molecule inhibitor as therapy for B-cell malignancies
Luke F Peterson1, Hanshi Sun1, Yihong Liu1
1Department of Internal Medicine/Division of Hematology/Oncology, University of Michigan School of Medicine and Comprehensive Cancer Center, Ann Arbor, MI;
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.
Insights
Targeting Usp9x and Usp24 deubiquitinases shows promise for treating multiple myeloma. Inhibiting these enzymes, particularly with novel compounds like EOAI3402143, induces cancer cell death and reduces tumor growth in preclinical models.
Area of Science:
- Biochemistry
- Oncology
- Molecular Biology
Background:
- Usp9x deubiquitinase is highly expressed in myeloma patients with poor prognosis.
- Usp9x is implicated in stabilizing the Mcl-1 survival protein, crucial for myeloma cell longevity.
Purpose of the Study:
- To investigate the therapeutic potential of targeting Usp9x and related deubiquitinases in multiple myeloma.
- To evaluate the efficacy of Usp9x/Usp24 inhibitors in preclinical models of myeloma.
Main Methods:
- Utilized Usp9x inhibitor WP1130 and short hairpin RNA (shRNA) for gene knockdown.
- Assessed compensatory upregulation of Usp24 in Usp9x-depleted cells.
- Developed and tested novel Usp9x/Usp24 inhibitor EOAI3402143 in mouse models.
Main Results:
- WP1130 induced apoptosis and reduced Mcl-1 levels in myeloma cells.
- Usp9x knockdown led to transient apoptosis, followed by compensatory Usp24 upregulation and sustained growth reduction.
- Direct Usp24 knockdown induced significant myeloma cell death by reducing Mcl-1.
- EOAI3402143 demonstrated dose-dependent inhibition of Usp9x/Usp24, increased apoptosis, and regressed myeloma tumors in mice.
- Usp24 overexpression was observed in drug-refractory myeloma and other B-cell malignancies.
Conclusions:
- Usp9x and Usp24 play critical roles in myeloma cell survival and Mcl-1 regulation.
- Small-molecule inhibitors targeting Usp9x and Usp24 exhibit significant therapeutic potential for multiple myeloma.
- Usp24 may be a key player in drug-refractory myeloma, suggesting dual Usp9x/Usp24 inhibition as a therapeutic strategy.
Related Concept Videos
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
02:34Inhibition of Cdk Activity
02:58Regulated Protein Degradation
Protein degradation plays two important roles in the cells. It helps to protect cells from misfolded or damaged proteins before they lead to a...