Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, 3800, Australia.
Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, 3800, Australia.
Nat Commun. 2023 Jul 27;14(1):4524. doi: 10.1038/s41467-023-40170-8.
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.
蛋白酪氨酸磷酸酶 1B（PTP1B）和 N2（PTPN2）的抑制作用已成为增强 T 细胞抗肿瘤免疫的一种令人兴奋的方法。ABBV-CLS-484 是一种正在进行的实体瘤临床试验中的 PTP1B/PTPN2 抑制剂。在这里，我们探索了相关小分子抑制剂化合物 182 的治疗潜力。我们证明，化合物 182 是一种高度有效和选择性的 PTP1B 和 PTPN2 的活性位点竞争性抑制剂，可增强 T 细胞的募集和激活，并抑制小鼠肿瘤的生长，而不会促进明显的免疫相关毒性。在免疫原性肿瘤中增强的抗肿瘤免疫可以归因于 T 细胞中 PTP1B/PTPN2 的抑制，而在冷肿瘤中，化合物 182 对肿瘤细胞和 T 细胞都产生了直接作用。重要的是，用化合物 182 治疗使原本耐药的肿瘤对 α-PD-1 治疗敏感。我们的发现为小分子 PTP1B 和 PTPN2 抑制剂增强抗肿瘤免疫和对抗癌症奠定了基础。
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