TCPTP inhibition as a novel therapeutic strategy for esophageal squamous cell carcinoma: discovery and efficacy of COH29.

Esophageal squamous cell carcinoma (ESCC) is a malignant tumor that poses a serious threat to human health and is often associated with poor prognosis. Therefore, it is urgent to explore new therapeutic strategies to improve the survival rate of patients with ESCC. T cell protein tyrosine phosphatase (TCPTP) has been reported as a complicated factor in cancer. In this study, we found that TCPTP was highly expressed in ESCC tissues and suppression of TCPTP can effectively inhibit the proliferation of ESCC cells in vitro and in vivo. To identify potential TCPTP inhibitors, we employed a comprehensive research approach encompassing virtual screening, pull down assay, and cellular thermal shift assay. This led to the discovery of two promising candidates: COH29 and gallocatechin gallate (GCG). Both compounds showed inhibitory effects on ESCC cell proliferation, with COH29 displaying superior efficacy. Further enzyme kinetics assay and molecular dynamics simulations confirmed COH29's unique ability to bind to both the substrate and allosteric sites of TCPTP, making it a promising lead compound for future inhibitor development. Flow cytometry analysis revealed that COH29 treatment caused cell cycle arrest in the G1 phase in ESCC cells. In vivo studies further validated COH29's robust growth suppression of ESCC, highlighting its potential as a therapeutic agent.