8SKL

PTP1B in complex with 182

Summary for 8SKL

• Entry DOI: 10.2210/pdb8skl/pdb
• Descriptor: Tyrosine-protein phosphatase non-receptor type 1, CHLORIDE ION, SODIUM ION, ... (6 entities in total)
• Functional Keywords: phosphatase, hydrolase, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 38193.29

Authors

Kershaw, N.J.,Babon, J.J.,Chen, H.,Tiganis, T. (deposition date: 2023-04-20, release date: 2023-08-02, Last modification date: 2024-12-04)

Primary citation

Liang, S.,Tran, E.,Du, X.,Dong, J.,Sudholz, H.,Chen, H.,Qu, Z.,Huntington, N.D.,Babon, J.J.,Kershaw, N.J.,Zhang, Z.Y.,Baell, J.B.,Wiede, F.,Tiganis, T.
A small molecule inhibitor of PTP1B and PTPN2 enhances T cell anti-tumor immunity.
Nat Commun, 14:4524-4524, 2023

PubMed 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.

PubMed: 37500611
DOI: 10.1038/s41467-023-40170-8

Experimental method

X-RAY DIFFRACTION (1.55 Å)