Liang and Tran et al. assessed Compound 182, a small-molecule inhibitor of protein tyrosine phosphatases 1B and N2 (PTP1B and PTPN2). In various immunologically hot and cold murine cancer models, treatment inhibited tumor growth and increased TILs, with enhanced T cell activation, expansion, and cytotoxicity. Treatment also induced STAT-1 signaling in tumor cells in cold tumors, which further enhanced T cell recruitment and antitumor responses. Compound 182 sensitized resistant tumors to anti-PD-1 therapy, with combination therapy causing synergistic effects, and did not induce immune-related adverse events.
Contributed by Maartje Wouters
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.
Author Info: (1) Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, 3800, Australia. Department of Biochemistry and Molecular Biology, Monash University, Clayton, Vic
Author Info: (1) Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, 3800, Australia. Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, 3800, Australia. (2) Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, 3052, Australia. (3) Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, 3800, Australia. Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, 3800, Australia. (4) Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, 47907, USA. (5) Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, 3800, Australia. Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, 3800, Australia. (6) Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3052, Australia. Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, 3052, Australia. (7) Department of Chemistry, Purdue University, West Lafayette, IN, 47907, USA. (8) Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, 3800, Australia. Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, 3800, Australia. (9) Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3052, Australia. Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, 3052, Australia. (10) Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3052, Australia. Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, 3052, Australia. (11) Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, 47907, USA. Department of Chemistry, Purdue University, West Lafayette, IN, 47907, USA. (12) Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, 3052, Australia. Lyterian Therapeutics, South San Francisco, San Francisco, CA, 94080, USA. (13) Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, 3800, Australia. Florian.Wiede@monash.edu. Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, 3800, Australia. Florian.Wiede@monash.edu. (14) Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, 3800, Australia. Tony.Tiganis@monash.edu. Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, 3800, Australia. Tony.Tiganis@monash.edu.
