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
  • 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. [email protected].
  • 10. Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, 3800, Australia. [email protected].
  • 11. Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, 3800, Australia. [email protected].
  • 12. Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, 3800, Australia. [email protected].
  • # 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.

Products