Developing small molecule PTP4A3 inhibitors for ovarian cancer

Project SummaryOur objective is to develop small molecule inhibitors of the highly oncogenic protein tyrosine phosphatasePTP Aas a targeted therapy for ovarian cancerOvCaElevated levels of PTP AmRNA and protein in ovarian tumors correlate with disease progression and recurrencepoor patient prognosis and poor patient survivalGenetic depletion of PTP Ain cancer cells diminishes their ability to survivemigrate and form tumors in vivoConverselyPTP Aoverexpression increases tumor cell migrationinvasion and dissemination in multiple cancersincluding OvCaTaken togetherthese data suggest PTP Ais a novel oncogenic molecular target for OvCaCurrentlythere are no small molecule PTP Ainhibitors in clinical development for any type of cancerWe discovered the most potent known in vitro small molecule inhibitor of PTP Awhich has a Ki ofnMJMSiminophenylthienoc pyridineHHdioneJMSdisplayed no significant in vitro inhibition ofother protein phosphatases andkinases atMsuggesting considerable specificity towards PTP AJMSkilled OvCa cells grown asD spheroidsincluding those derived from high grade serous and drug resistant OvCa cell lineswith ECvalues as low asnMJMStreatment also block the migration of OvCa cells and decreased RhoA activityJMSdid not inhibit the growth of the human ovarian surface epithelial cells at concentrations at least up toMJMSmg kgdisplayed anticancer activity in a murine xenograft model of drug resistant OvCaTo improve the pharmaceutical properties of JMSwe have synthesized next generation analogs that have superior ICvalues for PTP Ain vitro and are computationally more drug likeKeViRx proposes to credential these analogs to identify which compound sshould be developed further as potential targeted therapeutics for OvCaWe propose three TasksTaskDefine the single agent actions of JMSanalogs in drug sensitive andresistant human OvCa in vitroTaskDetermine the interactions of JMSand its analogs with clinically approved drugs for the treatment of OvCa in vitroTaskInvestigate the maximum tolerated in vivo dosethe pharmacokinetics and preliminary antitumor efficacy of two selected JMSanalogsThese studies should position at least one small molecule PTP Ainhibitor for further Phase II SBIR funded development in GMP grade analog studies Project NarrativeThere is an urgent need for new treatment strategies for human ovarian cancerThis proposal seeks to investigate the pharmacological properties of newly discovered small molecules that inhibit a protein tyrosine phosphatasePTP Awhich is highly expressed in many forms of cancer including ovarian cancerIf successfulthis research may provide an innovative approach for the treatment of ovarian cancer