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Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors
Published on: July 17, 2020
Targeting ovarian cancer and endothelium with an allosteric PTP4A3 phosphatase inhibitor
Kelley E McQueeney1, Joseph M Salamoun2, James C Burnett2
1Department of Pharmacology, University of Virginia, Charlottesville, VA, USA.
Abstract:
Overexpression of protein tyrosine phosphatase PTP4A oncoproteins is common in many human cancers and is associated with poor patient prognosis and survival. We observed elevated levels of PTP4A3 phosphatase in 79% of human ovarian tumor samples, with significant overexpression in tumor endothelium and pericytes. Furthermore, PTP4A phosphatases appear to regulate several key malignant processes, such as invasion, migration, and angiogenesis, suggesting a pivotal regulatory role in cancer and endothelial signaling pathways. While phosphatases are attractive therapeutic targets, they have been poorly investigated because of a lack of potent and selective chemical probes. In this study, we disclose that a potent, selective, reversible, and noncompetitive PTP4A inhibitor, JMS-053, markedly enhanced microvascular barrier function after exposure of endothelial cells to vascular endothelial growth factor or lipopolysaccharide. JMS-053 also blocked the concomitant increase in RhoA activation and loss of Rac1. In human ovarian cancer cells, JMS-053 impeded migration, disrupted spheroid growth, and decreased RhoA activity. Importantly, JMS-053 displayed anticancer activity in a murine xenograft model of drug resistant human ovarian cancer. These data demonstrate that PTP4A phosphatases can be targeted in both endothelial and ovarian cancer cells, and confirm that RhoA signaling cascades are regulated by the PTP4A family.
Insights
A new inhibitor, JMS-053, targets protein tyrosine phosphatase PTP4A, crucial in ovarian cancer and angiogenesis. This drug enhances microvascular barrier function and shows anticancer activity in preclinical models.
Area of Science:
- Oncology
- Cell Biology
- Biochemistry
Background:
- Protein tyrosine phosphatase PTP4A oncoproteins are overexpressed in many human cancers, correlating with poor prognosis.
- PTP4A3 phosphatase is elevated in ovarian tumors, particularly in tumor endothelium and pericytes.
- PTP4A phosphatases regulate key malignant processes including invasion, migration, and angiogenesis.
Purpose of the Study:
- To investigate the role of PTP4A phosphatases in cancer and endothelial signaling.
- To identify and characterize a potent and selective chemical probe for PTP4A.
- To evaluate the therapeutic potential of a novel PTP4A inhibitor in ovarian cancer models.
Main Methods:
- Development and characterization of a selective PTP4A inhibitor, JMS-053.
- Assessment of JMS-053's effect on microvascular barrier function in endothelial cells.
- Analysis of RhoA and Rac1 activation in response to JMS-053.
- Evaluation of JMS-053's impact on ovarian cancer cell migration, spheroid growth, and RhoA activity.
- Testing JMS-053's anticancer efficacy in a murine xenograft model.
Main Results:
- JMS-053 markedly enhanced microvascular barrier function and blocked RhoA activation/Rac1 loss.
- JMS-053 impeded ovarian cancer cell migration, disrupted spheroid growth, and decreased RhoA activity.
- JMS-053 demonstrated anticancer activity in a drug-resistant ovarian cancer xenograft model.
- PTP4A phosphatases regulate RhoA signaling cascades in both endothelial and cancer cells.
Conclusions:
- PTP4A phosphatases are viable therapeutic targets in both endothelial and ovarian cancer cells.
- JMS-053 is a potent, selective inhibitor of PTP4A with demonstrated preclinical anticancer efficacy.
- Targeting PTP4A offers a promising strategy for combating ovarian cancer and related angiogenesis.
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