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

Shuwei Liang, Eric Tran, Xin Du, Jiajun Dong, Harrison Sudholz, Hao Chen, Zihan Qu, Nicholas D. Huntington, Jeffrey J. Babon, Nadia J. Kershaw, Zhong-Yin Zhang, Jonathan B. Baell, Florian Wiede () and Tony Tiganis ()
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Shuwei Liang: Monash University
Eric Tran: Monash University
Xin Du: Monash University
Jiajun Dong: Purdue University
Harrison Sudholz: Monash University
Hao Chen: Walter and Eliza Hall Institute of Medical Research
Zihan Qu: Purdue University
Nicholas D. Huntington: Monash University
Jeffrey J. Babon: Walter and Eliza Hall Institute of Medical Research
Nadia J. Kershaw: Walter and Eliza Hall Institute of Medical Research
Zhong-Yin Zhang: Purdue University
Jonathan B. Baell: Monash University
Florian Wiede: Monash University
Tony Tiganis: Monash University

Nature Communications, 2023, vol. 14, issue 1, 1-27

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-40170-8

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