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Next-Generation Cell-Active Inhibitors of the Undrugged Oncogenic PTP4A3 Phosphatase

John S Lazo1, Isabella K Blanco2, Nikhil R Tasker2

  • 1Departments of Pharmacology (J.S.L., I.K.B., S.R.G., D.J.H., E.R.S.) and Chemistry (J.S.L., R.L.M., K.-L.H.), University of Virginia, Charlottesville, Virginia; and Department of Chemistry (N.R.T., E.J.R., J.C.B., P.W.), University of Pittsburgh, Pittsburgh, Pennsylvania lazo@virginia.edu.

The Journal of Pharmacology and Experimental Therapeutics
|October 12, 2019
PubMed

Insights

New small molecules selectively inhibit oncogenic PTP4A phosphatases, showing cytotoxicity against ovarian and breast cancer cells without generating reactive oxygen species. These findings highlight a promising chemotype for future cancer therapy development.

Area of Science:

  • Biochemistry and Molecular Biology
  • Cancer Research
  • Medicinal Chemistry

Background:

  • Oncogenic protein tyrosine phosphatases (PTPs) are frequently overexpressed in human cancers, presenting significant therapeutic challenges.
  • The PTP4A phosphatase family plays a crucial role in fundamental malignant processes, making it a key target for cancer drug development.
  • Existing PTP inhibitors face challenges, necessitating the exploration of novel chemotypes and mechanisms of action.

Purpose of the Study:

  • To elucidate the mechanism of action of the novel PTP4A inhibitor JMS-053 and investigate its chemotype, with a focus on the role of oxidation.
  • To synthesize and evaluate new analogs of JMS-053 for improved specificity and efficacy against PTP4A phosphatases.
  • To assess the cytotoxic effects of these inhibitors on relevant cancer cell models and determine their dependence on PTP4A expression.

Main Methods:

  • Synthesis and characterization of JMS-053 analogs, including 7-imino-5-methyl-2-phenylthieno[3,2-c]pyridine-4,6(5H,7H)-dione (NRT-870-59).
  • In vitro inhibition assays using PTP4A3 and its mutants, as well as CDC25B, to determine specificity.
  • Cytotoxicity assays using three-dimensional spheroid cultures of human ovarian and breast cancer cells, and colony formation assays.
  • Assessment of reactive oxygen species (ROS) generation using in vitro and cellular assays.
  • Mass spectrometry to detect potential oxidation of the catalytic cysteine residue.
  • Gene expression profiling to analyze cellular responses to inhibitor treatment.

Main Results:

  • JMS-053 and its analogs demonstrated potent in vitro inhibition of PTP4A3.
  • NRT-870-59 exhibited unique specificity for PTP4A3 over a PTP4A3 mutant and CDC25B, acting as a reversible inhibitor.
  • All tested thienopyridinediones showed cytotoxicity against ovarian and breast cancer spheroids, with inhibition of colony formation dependent on PTP4A3 expression.
  • JMS-053 and NRT-870-59 did not generate significant ROS in vitro or in cancer cells, and mass spectrometry confirmed no oxidation of PTP4A3's catalytic cysteine.
  • Gene expression profiling indicated that JMS-053 treatment phenocopied PTP4A3 loss without inducing oxidative stress.

Conclusions:

  • Selective small molecule inhibition of PTP4A phosphatases is achievable with the thienopyridinedione chemotype.
  • These novel inhibitors are effective against ovarian and breast cancer cells and do not rely on ROS generation, suggesting a favorable safety profile.
  • The findings support the further investigation of this class of reversible PTP4A inhibitors as potential lead compounds for cancer therapy.

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