A small molecule inhibitor of PTP1B and PTPN2 enhances T cell anti-tumor immunity

Liang, S; Tran, E; Du, X; Dong, J; Sudholz, H; Chen, H; Qu, Z; Huntington, ND; Babon, JJ; Kershaw, NJ; Zhang, ZY; Baell, JB; Wiede, F; Tiganis, T

Author(s): Liang, S; Tran, E; Du, X; Dong, J; Sudholz, H; Chen, H; Qu, Z; Huntington, ND; Babon, JJ; Kershaw, NJ; Zhang, ZY; Baell, JB; Wiede, F; Tiganis, T;
Details: Publication Year 2023-07-27,Volume 14,Issue #1,Page 4524
Journal Title: Nature Communications
Abstract: The inhibition of protein tyrosine phosphatases 1B (PTP1B) and N2 (PTPN2) has emerged as an exciting approach for bolstering T cell anti-tumor immunity. ABBV-CLS-484 is a PTP1B/PTPN2 inhibitor in clinical trials for solid tumors. Here we have explored the therapeutic potential of a related small-molecule-inhibitor, Compound-182. We demonstrate that Compound-182 is a highly potent and selective active site competitive inhibitor of PTP1B and PTPN2 that enhances T cell recruitment and activation and represses the growth of tumors in mice, without promoting overt immune-related toxicities. The enhanced anti-tumor immunity in immunogenic tumors can be ascribed to the inhibition of PTP1B/PTPN2 in T cells, whereas in cold tumors, Compound-182 elicited direct effects on both tumor cells and T cells. Importantly, treatment with Compound-182 rendered otherwise resistant tumors sensitive to α-PD-1 therapy. Our findings establish the potential for small molecule inhibitors of PTP1B and PTPN2 to enhance anti-tumor immunity and combat cancer.
Publisher: NPG
Keywords: Mice; Animals; *Protein Tyrosine Phosphatase, Non-Receptor Type 2/genetics/metabolism; Phosphoric Monoester Hydrolases; *Neoplasms/drug therapy; Protein Tyrosine Phosphatase, Non-Receptor Type 1/genetics/metabolism; T-Lymphocytes/metabolism; Enzyme Inhibitors/pharmacology/chemistry
Research Division(s): Structural Biology
PubMed ID: 37500611
Publisher's Version: https://doi.org/10.1038/s41467-023-40170-8
Open Access at Publisher's Site: https://doi.org/10.1038/s41467-023-40170-8
Terms of Use/Rights Notice: Refer to copyright notice on published article.
Documents: s41467-023-40170-8.pdf - (7.15MB, application/pdf)

Creation Date: 2023-08-04 12:44:12

Last Modified: 2023-08-04 01:36:19