Next Generation Potent Cell‐active Inhibitors of the Oncogenic PTP4A3 Phosphatase

Abstract

High grade serous ovarian cancer and triple negative breast cancer respond poorly to existing drugs and, thus, demand new therapies. The protein tyrosine phosphatase PTP4A3 (Phosphatase of Regenerating Liver‐3, PRL‐3) is overexpressed in these diseases. Moreover, PTP4A3 promotes cancer cell migration and invasion and is believed to be the most oncogenic of all tyrosine phosphatases. We recently synthesized the novel iminothienopyridone, JMS‐053, and demonstrated that it is a specific, reversible, allosteric, and cell active small molecule PTP4A3 inhibitor with an in vitro IC50 for PTP4A3 of 30 nM. The water solubility of JMS‐053 is limited, however. Therefore, we synthesized twenty next generation analogs to improve aqueous solubility and to aid in determining the structure activity relationship for the chemotype, the PTP4A3 binding site, and the mechanism of inhibition. Seventeen analogs retained potent in vitro PTP4A3 inhibition with IC50 values <100 nM. Four compounds, EJR‐866‐36, EJR‐866‐68, EJR‐855‐81, and NRT‐892‐04, had in vitro PTP4A3 IC50values of <40 nM. EJR‐866‐75 and NRT‐870‐59 were computationally more drug‐like than JMS‐053. EJR‐855‐81, NRT‐870‐59, EJR‐866‐75, and NRT‐870‐59 were cytotoxic to human Hs578T breast cancer and OVCAR4 ovarian cancer 3D spheroid tumor cells grown in vitro with IC50 values below 20 mM. To further expand the mechanistic activity of this class of inhibitors, we have synthesized four third‐generation analogs of JMS‐053, which combine the iminothienopyridone motif with a chemical moiety capable of binding a E3 ubiquitin ligase that will accelerate the intracellular degradation of PTP4A3. One of these novel compounds, EJR‐887‐35, had a PTP4A3 in vitro IC50 value of 107 nM and retained cytotoxicity to Hs578T and OVCAR4 cells with IC50 values below 20 mM in 3D spheroid tumors. These results suggest the iminothienopyridone chemotype could be valuable for the development of the first potent, cell active PTP4A3 phosphatase inhibitors directed against breast and ovarian cancer.Support or Funding InformationDepartment of Defense (Award W81XWH‐18‐1‐0011, BC170507), NIH Grant P30 CA044579 and S10 OD021723, and the Fiske Drug Discovery Fund.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.