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Biomolecules
Volume 11
Issue 7
10.3390/biom11070969
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Article

Credentialing and Pharmacologically Targeting PTP4A3 Phosphatase as a Molecular Target for Ovarian Cancer

by
John S. Lazo
1,2,*,
Elizabeth R. Sharlow
1,2,*,
Robert Cornelison
1,2,
Duncan J. Hart
1,
Danielle C. Llaneza
1,
Anna J. Mendelson
1,
Ettore J. Rastelli
3,
Nikhil R. Tasker
3,
Charles N. Landen, Jr.
4 and
Peter Wipf
3
1
Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA
2
KeViRx, Inc., Charlottesville, VA 22904, USA
3
Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA
4
Department of Obstetrics and Gynecology, University of Virginia, Charlottesville, VA 22908, USA
*
Authors to whom correspondence should be addressed.
Biomolecules 2021, 11(7), 969; https://doi.org/10.3390/biom11070969
Submission received: 11 June 2021 / Revised: 26 June 2021 / Accepted: 28 June 2021 / Published: 30 June 2021
(This article belongs to the Collection Feature Papers in Enzymology)
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Abstract

High grade serous ovarian cancer (OvCa) frequently becomes drug resistant and often recurs. Consequently, new drug targets and therapies are needed. Bioinformatics-based studies uncovered a relationship between high Protein Tyrosine Phosphatase of Regenerating Liver-3 (PRL3 also known as PTP4A3) expression and poor patient survival in both early and late stage OvCa. PTP4A3 mRNA levels were 5–20 fold higher in drug resistant or high grade serous OvCa cell lines compared to nonmalignant cells. JMS-053 is a potent allosteric small molecule PTP4A3 inhibitor and to explore further the role of PTP4A3 in OvCa, we synthesized and interrogated a series of JMS-053-based analogs in OvCa cell line-based phenotypic assays. While the JMS-053 analogs inhibit in vitro PTP4A3 enzyme activity, none were superior to JMS-053 in reducing high grade serous OvCa cell survival. Because PTP4A3 controls cell migration, we interrogated the effect of JMS-053 on this cancer-relevant process. Both JMS-053 and CRISPR/Cas9 PTP4A3 depletion blocked cell migration. The inhibition caused by JMS-053 required the presence of PTP4A3. JMS-053 caused additive or synergistic in vitro cytotoxicity when combined with paclitaxel and reduced in vivo OvCa dissemination. These results indicate the importance of PTP4A3 in OvCa and support further investigations of the lead inhibitor, JMS-053.
Keywords: ovarian cancer; protein tyrosine phosphatase; drug target validation; cell migration; IL-6; drug synergy ovarian cancer; protein tyrosine phosphatase; drug target validation; cell migration; IL-6; drug synergy

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MDPI and ACS Style

Lazo, J.S.; Sharlow, E.R.; Cornelison, R.; Hart, D.J.; Llaneza, D.C.; Mendelson, A.J.; Rastelli, E.J.; Tasker, N.R.; Landen, C.N., Jr.; Wipf, P. Credentialing and Pharmacologically Targeting PTP4A3 Phosphatase as a Molecular Target for Ovarian Cancer. Biomolecules 2021, 11, 969. https://doi.org/10.3390/biom11070969

AMA Style

Lazo JS, Sharlow ER, Cornelison R, Hart DJ, Llaneza DC, Mendelson AJ, Rastelli EJ, Tasker NR, Landen CN Jr., Wipf P. Credentialing and Pharmacologically Targeting PTP4A3 Phosphatase as a Molecular Target for Ovarian Cancer. Biomolecules. 2021; 11(7):969. https://doi.org/10.3390/biom11070969

Chicago/Turabian Style

Lazo, John S., Elizabeth R. Sharlow, Robert Cornelison, Duncan J. Hart, Danielle C. Llaneza, Anna J. Mendelson, Ettore J. Rastelli, Nikhil R. Tasker, Charles N. Landen, Jr., and Peter Wipf. 2021. "Credentialing and Pharmacologically Targeting PTP4A3 Phosphatase as a Molecular Target for Ovarian Cancer" Biomolecules 11, no. 7: 969. https://doi.org/10.3390/biom11070969

APA Style

Lazo, J. S., Sharlow, E. R., Cornelison, R., Hart, D. J., Llaneza, D. C., Mendelson, A. J., Rastelli, E. J., Tasker, N. R., Landen, C. N., Jr., & Wipf, P. (2021). Credentialing and Pharmacologically Targeting PTP4A3 Phosphatase as a Molecular Target for Ovarian Cancer. Biomolecules, 11(7), 969. https://doi.org/10.3390/biom11070969

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