Synthesis and structure-activity optimization of azepane-containing derivatives as PTPN2/PTPN1 inhibitors.

Protein tyrosine phosphatases PTPN2 and PTPN1 (also known as PTP1B) have been implicated in a number of intracellular signaling pathways of immune cells. The inhibition of PTPN2 and PTPN1 has emerged as an attractive approach to sensitize T cell anti-tumor immunity. Two small molecule inhibitors have been entered the clinic. Here we report the design and development of compound 4, a novel small molecule PTPN2/N1 inhibitor demonstrating nanomolar inhibitory potency, good in vivo oral bioavailability, and robust in vivo antitumor efficacy.

Protein tyrosine phosphatase PTPN2 regulates TGF-ß signaling through Smad4 dephosphorylation.

Transforming Growth Factor beta (TGF-ß) is a multifunctional cytokine that regulates cell proliferation, differentiation, and apoptosis. Dysregulation of the TGF-ß signaling is one of the major mechanisms underlying tumor progression. We have previously reported that anaplastic lymphoma kinase (ALK) phosphorylates Smad4 at Tyr95, which compromises the DNA-binding ability of Smad4 and thus renders ALK-positive cancer cells resistant to TGF-ß tumor-suppressive action. In this study, we demonstrated that tyrosine phosphatase PTPN2 positively regulated TGF-ß signaling through dephosphorylating Smad4 at the Tyr95 site. Both in vitro and cell-based assays revealed that PTPN2 bound to and dephosphorylated Smad4, thereby preserving the DNA-binding ability of Smad4. Furthermore, overexpression of PTPN2 restored TGF-ß transcriptional and growth inhibitory responses in ALK-positive cancer cells. Consistently, Spermidine, an activator of PTPN2, also promoted TGF-ß-induced gene expression, apoptosis, and anti-proliferation effect. Taken together, we revealed that PTPN2 functioned as a tumor suppressor to antagonize the inhibitory effect of tyrosine phosphorylation of Smad4 and to ensure the proper TGF-ß growth inhibitory signaling in cancer cells.