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

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

  • Nat Commun. 2023 Jul 27;14(1):4524. doi: 10.1038/s41467-023-40170-8.
Shuwei Liang # 1 2,  Eric Tran # 3,  Xin Du 1 2,  Jiajun Dong 4,  Harrison Sudholz 1 2,  Hao Chen 5 6,  Zihan Qu 7,  Nicholas D Huntington 1 2,  Jeffrey J Babon 5 6,  Nadia J Kershaw 5 6,  Zhong-Yin Zhang 4 7,  Jonathan B Baell 3 8,  Florian Wiede 9 10,  Tony Tiganis 11 12
Affiliations

Affiliations

  • 1 Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, 3800, Australia.
  • 2 Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, 3800, Australia.
  • 3 Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, 3052, Australia.
  • 4 Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, 47907, USA.
  • 5 Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3052, Australia.
  • 6 Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, 3052, Australia.
  • 7 Department of Chemistry, Purdue University, West Lafayette, IN, 47907, USA.
  • 8 Lyterian Therapeutics, South San Francisco, San Francisco, CA, 94080, USA.
  • 9 Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, 3800, Australia. Florian.Wiede@monash.edu.
  • 10 Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, 3800, Australia. Florian.Wiede@monash.edu.
  • 11 Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, 3800, Australia. Tony.Tiganis@monash.edu.
  • 12 Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, 3800, Australia. Tony.Tiganis@monash.edu.
  • # Contributed equally.
PMID: 37500611 DOI: 10.1038/s41467-023-40170-8
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.

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