UC San Diego

In recent clinical studies, the success of immune checkpoint inhibitors to modulate the immune system in metastatic melanoma patients has shown a great response rate. However, there are still subsets of patients which are only partially responsive or non-responsive towards this cutting-edge immunotherapy. This unpredictable therapeutic response has caused a set-back to treating this deadly disease. A phosphatase, Protein Tyrosine Phosphatase Non-Receptor Type 2 (PTPN2) has been implicated in reducing tumor cells responses to immunotherapy; deletion of PTPN2 in tumor cells positively influenced the efficacy of immunotherapy by increasing interferon-γ-mediated effects on antigen presentation and growth suppression. By employing a virtual high throughput screening (vHTS) and computer-aided structure-drug design, PTPN2 inhibitors were designed and synthesized. Ten small molecule inhibitors of PTPN2 were analyzed in murine melanoma models and three inhibitors, ID_5, ID_7, and ID_9, were found to have potent activity against PTPN2. Ptpn2 inhibition by these lead compounds induced the intracellular Interferon-γ (IFN-γ) signaling pathway. Furthermore, these inhibitors enhanced Stat1 phosphorylation, defining the underlying mechanism of inhibitors in Interferon signaling. Additional cell viability assays, quantitative reverse transcription PCR (RT-qPCR) analysis, and western blotting of rationally designed Ptpn2 inhibitors demonstrated their in vitro anti-melanoma cancer activities with no apparent toxicity in murine cell lines. While further investigations are needed using in vivo models, these data altogether indicate that Ptpn2 small molecule inhibitors are novel agents that may enhance therapeutic responses in melanoma cancer which are resistant to currently available immunotherapies.