Abstract A83: Profiling potent, novel protein tyrosine phosphatase 4A3 small molecule inhibitors for ovarian cancer.

Abstract

Abstract PTP4A3 (also known as PRL-3) is a unique protein tyrosine phosphatase that is highly expressed in human ovarian cancer patient samples. Genetic knockdown studies implicate PTP4A3 in ovarian cancer tumorigenesis and the maintenance of the malignant phenotype. Interestingly, cBioportal data mining reveals that PTP4A3 is one of the most highly amplified genes in ovarian cancer, implicating PTP4A3 as a novel, and to date, largely underexplored potential molecular therapeutic target. Unfortunately, the lack of potent and selective PTP4A3 inhibitors impedes the validation of PTP4A3 as a drug target for ovarian cancer. To drive target validation studies and complement our ongoing cell-based genetic PTP4A3 knockdown strategies, we have developed novel PTP4A3 small molecule inhibitors to delineate its mechanistic role in ovarian cancer and therapeutic potential as a drug target. We resynthesized the most potent published PTP4A3 inhibitor (thienopyridone or JMS-631-050). Concurrently, we discovered a new, more active thienopyridone analog, JMS-631-053. Additionally, we identified a structurally related inactive analog, JMS-557-038, which could be used as a pharmacologically powerful control. JMS-631-050 and JMS-631-053 inhibited recombinant PTP4A3 in vitro phosphatase activity with IC50 values of 138 and 7 nM, respectively. We then profiled the impact of JMS-631-050, JMS-631-053 and JMS-557-038 on cell adhesion-based survival using a panel of eight ovarian cancer cell lines, which included a representative high serous grade ovarian cancer cell line (i.e., OVCAR4) and several drug sensitive/resistant cell line pairs. In all ovarian cancer cells lines tested, both JMS-631-050 and JMS-631-053 inhibited cell adhesion-mediated survival. However, JMS-631-053 displayed more potent cell-based effects than JMS-631-050 in all cell lines evaluated. A2780 cells were the most sensitive to JMS-631-053 effects (EC50=0.60±0.2 μM). Significantly, OVCAR4 cells were also highly sensitive to JMS-631-053 with an EC50=1.5±0.3 μM. Both JMS-631-050 and JMS-631-053 maintained cell-based activity when evaluated in three dimensional cell culture models. As expected the PTP4A3 inactive analog, JMS-557-038 had no effect on cell-adhesion-mediated survival (EC50s>50 μM) in any of the ovarian cancer cell lines tested. Thus, JMS-631-050 and JMS-631-053 are attractive chemotypes for further evaluation as single agents for ovarian cancer. Moreover, as the drug resistant cell lines A2780CP20 and HeyA8MDR retained sensitivity to JMS-631-050 and JMS-631-053, these chemotypes are under evaluation in combination studies using existing ovarian cancer therapies. Hence, JMS-631-050 and JMS-631-053 will be valuable reagents for further validation of PTP4A3 as an ovarian cancer target as well as potential leads for future drug dis. Citation Format: Elizabeth R. Sharlow, Joseph M. Salamoun, Kelley E. McQueeney, Sophie Lewandowski, Jennifer Bryant, Alex Cheung, Paula Pekic, Charles N. Landen, Jr., Peter Wipf, John S. Lazo. Profiling potent, novel protein tyrosine phosphatase 4A3 small molecule inhibitors for ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr A83.