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

<div class='caption-title'>Compound 182 is a reversible, competitive, active site inhibitor of PTP1B and PTPN2.</div>
<div class='caption-title'>Compound 182 promotes T cell signaling.</div>
<div class='caption-title'>Compound 182 represses AT3-OVA mammary tumor growth.</div>
Liang S, Tran E, Du X, Dong J, Sudholz H, Chen H, Qu Z, Huntington ND, Babon JJ, Kershaw NJ, Zhang ZY, Baell JB, Wiede F, Tiganis T
OpenAccess logo Nat Commun 14 4524 (2023)
Cited: 20 times
EuropePMC logo PMID: 37500611

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.

Reviews citing this publication (10)

  1. IL-15 and N-803 for HIV Cure Approaches. Howard JN, Bosque A. Viruses 15 1912 (2023)
  2. Protein tyrosine phosphatase 1B in metabolic diseases and drug development. Delibegović M, Dall'Angelo S, Dekeryte R. Nat Rev Endocrinol 20 366-378 (2024)
  3. Targeting Protein Tyrosine Phosphatases to Improve Cancer Immunotherapies. Salmond RJ. Cells 13 231 (2024)
  4. From Tyrosine Kinases to Tyrosine Phosphatases: New Therapeutic Targets in Cancers and Beyond. Zhou Y, Yao Z, Lin Y, Zhang H. Pharmaceutics 16 888 (2024)
  5. Immunotherapeutic implications of negative regulation by protein tyrosine phosphatases in T cells: the emerging cases of PTP1B and TCPTP. Perez-Quintero LA, Abidin BM, Tremblay ML. Front Med (Lausanne) 11 1364778 (2024)
  6. Focusing on CD8+ T-cell phenotypes: improving solid tumor therapy. Yao Z, Zeng Y, Liu C, Jin H, Wang H, Zhang Y, Ding C, Chen G, Wu D. J Exp Clin Cancer Res 43 266 (2024)
  7. Protein Tyrosine Phosphatase 1B (PTP1B): A Comprehensive Review of Its Role in Pathogenesis of Human Diseases. Kołodziej-Sobczak D, Sobczak Ł, Łączkowski KZ. Int J Mol Sci 25 7033 (2024)
  8. Protein tyrosine phosphatases as emerging targets for cancer immunotherapy. Qu Z, Dong J, Zhang ZY. Br J Pharmacol (2023)
  9. Recent Developments in the Role of Protein Tyrosine Phosphatase 1B (PTP1B) as a Regulator of Immune Cell Signalling in Health and Disease. Read NE, Wilson HM. Int J Mol Sci 25 7207 (2024)
  10. Therapeutic potential of targeting protein tyrosine phosphatases in liver diseases. Wang A, Zhang Y, Lv X, Liang G. Acta Pharm Sin B 14 3295-3311 (2024)

Articles citing this publication (10)

  1. The latency-reversing agent HODHBt synergizes with IL-15 to enhance cytotoxic function of HIV-specific T cells. Copertino DC, Holmberg CS, Weiler J, Ward AR, Howard JN, Levinger C, Pang AP, Corley MJ, Dündar F, Zumbo P, Betel D, Gandhi RT, McMahon DK, Bosch RJ, Linden N, Macatangay BJ, Cyktor JC, Eron JJ, Mellors JW, Kovacs C, Benko E, Bosque A, Jones RB, AIDS Clinical Trials Group (ACTG) A5321 Team. JCI Insight 8 e169028 (2023)
  2. IKAROS and AIOLOS directly regulate AP-1 transcriptional complexes and are essential for NK cell development. Goh W, Sudholz H, Foroutan M, Scheer S, Pfefferle A, Delconte RB, Meng X, Shen Z, Hennessey R, Kong IY, Schuster IS, Andoniou CE, Davis MJ, Hediyeh-Zadeh S, Souza-Fonseca-Guimaraes F, Parish IA, Beavis P, Thiele D, Chopin M, Degli-Esposti MA, Cursons J, Kallies A, Rautela J, Nutt SL, Huntington ND. Nat Immunol 25 240-255 (2024)
  3. Mulberry Leaf Compounds and Gut Microbiota in Alzheimer's Disease and Diabetes: A Study Using Network Pharmacology, Molecular Dynamics Simulation, and Cellular Assays. Bai X, Zhao X, Liu K, Yang X, He Q, Gao Y, Li W, Han W. Int J Mol Sci 25 4062 (2024)
  4. X-CHIME enables combinatorial, inducible, lineage-specific and sequential knockout of genes in the immune system. LaFleur MW, Lemmen AM, Streeter ISL, Nguyen TH, Milling LE, Derosia NM, Hoffman ZM, Gillis JE, Tjokrosurjo Q, Markson SC, Huang AY, Anekal PV, Montero Llopis P, Haining WN, Doench JG, Sharpe AH. Nat Immunol 25 178-188 (2024)
  5. Farrerol alleviates insulin resistance and hepatic steatosis of metabolic associated fatty liver disease by targeting PTPN1. Gao J, Cang X, Liu L, Lin J, Zhu S, Liu L, Liu X, Zhu J, Xu C. J Cell Mol Med 28 e70096 (2024)
  6. The HIV latency reversing agent HODHBt inhibits the phosphatases PTPN1 and PTPN2. Howard JN, Zaikos TD, Levinger C, Rivera E, McMahon EK, Holmberg CS, Terao J, Sanz M, Copertino DC, Wang W, Soriano-Sarabia N, Jones RB, Bosque A. JCI Insight 9 e179680 (2024)
  7. Ursonic acid from medicinal herbs inhibits PRRSV replication through activation of the innate immune response by targeting the phosphatase PTPN1. Yang Y, Gao Y, Sun H, Bai J, Zhang J, Zhang L, Liu X, Sun Y, Jiang P. Vet Res 55 67 (2024)
  8. PTPRK regulates glycolysis and de novo lipogenesis to promote hepatocyte metabolic reprogramming in obesity. Gilglioni EH, Li A, St-Pierre-Wijckmans W, Shen TK, Pérez-Chávez I, Hovhannisyan G, Lisjak M, Negueruela J, Vandenbempt V, Bauzá-Martinez J, Herranz JM, Ezeriņa D, Demine S, Feng Z, Vignane T, Otero Sanchez L, Lambertucci F, Prašnická A, Devière J, Hay DC, Encinar JA, Singh SP, Messens J, Filipovic MR, Sharpe HJ, Trépo E, Wu W, Gurzov EN. Nat Commun 15 9522 (2024)
  9. Pan-cancer analysis revealing that PTPN2 is an indicator of risk stratification for acute myeloid leukemia. Wang X, Wu S, Sun L, Jin P, Zhang J, Liu W, Zhan Z, Wang Z, Liu X, He L. Sci Rep 13 18372 (2023)
  10. The combination of a PTP1B inhibitor, TNFR2 blocker, and PD‑1 antibody suppresses the progression of non‑small cell lung cancer tumors by enhancing immunocompetence. Gui H, Nie Y, Yuan H, Jing Q, Li L, Zhu L, Chen S, Wang M, Wan Q, Lv H, Nie Y, Zhang X. Oncol Rep 52 149 (2024)


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