Investigational inhibitors of PTP4A3 phosphatase as antineoplastic agents.

Introduction: Protein tyrosine (Tyr) phosphatases have been implicated in many diseases, most notably in cancer. While there are a significant number of clinically approved inhibitors of protein Tyr kinases, there are no drugs specifically targeting protein Tyr phosphatases in clinical use despite the attractiveness of the molecular target.

Areas Covered: This review examines the investigational challenges in identifying Tyr phosphatase inhibitors using the oncogenic phosphatase PTP4A3 as a prototype. The article includes a review of the structure, functionality and validation of PTP4A3 as a cancer target. It also provides an evaluation of existing small molecule and antibody inhibitors and provides new computational guidance for potentially more potent small molecule inhibitors.

Expert Opinion: Tyr phosphatases, like PTP4A3, represent high value but ignored molecular targets for the treatment of cancer and other diseases. Although phosphatases are challenging targets, it seems likely that drug-like inhibitors of this important enzyme family would complement the growing number of protein Tyr kinase inhibitors. Animal models are beginning to provide validation for PTP4A3 as a molecular target for cancer progression and metastasis. The authors posit that greater efforts should be directed towards identifying Tyr phosphatase inhibitors for lead optimization and tool compounds to assist in interrogating and validating phosphatase involvement in physiological and pathological processes.