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

Author:

Liang Shuwei,Tran EricORCID,Du Xin,Dong Jiajun,Sudholz HarrisonORCID,Chen Hao,Qu Zihan,Huntington Nicholas D.ORCID,Babon Jeffrey J.ORCID,Kershaw Nadia J.ORCID,Zhang Zhong-YinORCID,Baell Jonathan B.ORCID,Wiede Florian,Tiganis TonyORCID

Abstract

AbstractThe 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.

Funder

Department of Health | National Health and Medical Research Council

United States Department of Defense | United States Army | U.S. Army Corps of Engineers

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary

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